NIH Bets $1,434,188 That Synapses Don't Store Memories

In today's news we read a press release from the National Institute of Health entitled "NIH supports 106 grants featuring high-risk, high-reward research."  The research discussed are projects with a high risk of failure, but which might yield a high reward if they succeed.  We read the following: "Supported research this year includes understanding how long-term memory might be encoded in the shape of folded DNA in our neurons, mining data from unconventional sources to reveal social determinants of suicide, establishing new paradigms to address the functional consequences of health disparities in drug development, and looking at the impact of high school and collegiate athlete injuries on long-term health." 

The first project mentioned (apparently NIH Project # 1DP2MH129985-01 discussed on this page) is relevant to the question of whether scientists currently have any credible theory of the storage of long-term human memories.  For many decades scientists have been telling us that long-term memories are stored in synapses.  There has never been any robust evidence or any credible detailed theory backing up such an idea.  Everything we know about synapses suggests that they are totally unsuitable for the task of storing memories that can last for 50 years. For example, the proteins in synapses have average lifetimes of only a few weeks or less. Synapses have a high degree of structural dependency on dendritic spines, which are short-lived things that do not last for years.  No one has ever proven that a synapse lasts for years, and we have good reason for believing they do not last for years. 

What is interesting about this NIH Project # 1DP2MH129985-01 is that it is a kind of "heresy" project that is totally contrary to the "orthodoxy" that our neuroscientists have been spouting for decades about memory.  The project has the wildly speculative title "The epigenetic encoding of learning and memory," which is a research project title as speculative as "Extraterrestrial UFO mother-ships near Jupiter."  The idea that human memories are encoded in the genome or the epigenome is an idea totally contrary to what neuroscientists have been telling us for decades, that memories are stored in synapses.  The genome and the epigenome are found in the center of cells. A synapse is a unit vastly tinier than a cell, outside of a cell or or on the outer edge of a cell.  In the visual below depicting a neuron (one of the cells in the brain), the brown circle at the center is the location of the genome and the epigenome, and synapses (too small to show) would be located around the orange parts on the edges:

We see from the project page that the NIH has granted $1,434,188 of public funds for this new project. The project page presents no detailed research project plan. We merely get a vague project description that leaves the researchers free to play around pretty much in any way they want.  That description often resorts to speculation stated as if it were fact. Here is the description (I'll put in boldface the very speculative parts that are not at all statements of fact):

"The nervous system requires tight control of transcription for processes such as learning and memory formation. The field of epigenetics seeks to understand how changes to gene transcription occur in response to environmental cues and external signals such as those that our brains experience during learning. This proposal lies at the intersection of neuroscience and epigenetics, with a particular focus on chromatin biology. Chromatin is the complex of DNA and the histone proteins that wrap up DNA into complex structures, recruit key transcriptional regulators, and in doing so, control gene expression. In recent years, it has become clear that disruptions to chromatin regulation lead to a range of neurological and mental health disorders such as post- traumatic stress disorder (PTSD). However, we have a limited understanding of how chromatin functions in the brain or how its disruption can lead to disease. We will apply the tools and techniques of the epigenetics field to the study of neuronal function. In doing so, we hope to elucidate the molecular mechanisms that allow our brains to perform incredibly complex tasks and how disruption of these mechanisms can lead to neuronal dysfunction. We propose overcome long-standing hurdles in the field using a combination of novel techniques to reveal how the epigenetic landscape encodes the transcriptional changes that underlie memory formation. Specifically, we seek to uncover the transcriptional signature of memory formation and memory maintenance within single neurons in an in vivo context. We then will examine the epigenetic underpinnings of this transcriptional signature and manipulate specific components of the chromatin environment to define their contribution to learning and memory maintenance. First, in order to elucidate the gene program associated with learning, we will use single-nucleus RNA-sequencing in combination with mouse models that label the specific neurons activated during learning. This will allow us to examine the transcriptional programs activated in neurons that form a memory engram compared to their neighboring cells at various times after learning. Next, we will employ a quantitative biochemical approach uniquely available to our group as part of the Epigenetics Institute to characterize the chromatin landscape changes the occur during memory formation, memory maintenance, and reversal learning. Finally, we will modify the chromatin landscape by manipulating specific histone proteins in combination with numerous sequencing approaches to elucidate how chromatin controls learning and the transcriptional program. Employing this novel combination of techniques will allow us to uncover the mechanisms through which the epigenome encodes information within neurons to modify behavior both in the context of normal learning and in the context of maladaptive responses that lead to disorders such as PTSD. If successful, these methods will 1) identify the transcriptional signature that encodes a memory in neurons, 2) map how this signature is encoded by specific epigenetic regulatory mechanisms, and 3) define how the chromatin landscape affects memory formation and contributes to mental health disorders."

What we have here (in the boldface parts) are statements of an unfounded and wildly speculative theory: the contrarian idea that memories are stored in chromatin (consisting of DNA and proteins surrounding it) and an  associated epigenome (consisting of kind of chemical marks next to parts of DNA) . Such statements are made in a matter-of-fact manner, as if such a "yet-to-reach-first-base" theory was fact.  The not-yet-popular theory being suggested is one very different from what neuroscientists have been claiming for decades.  For decades, neuroscientists have been telling us that memory formation occurs through "synapse strengthening," not through "transcriptional changes."  We see no mention of the word "synapses" or "synaptic" in the quotation above. 

The boldface above states an idea that makes no sense. "Transcriptional signatures" are transitory fleeting fluctuating biomarkers of the rates at which particular genes are being expressed. Conversely, for a long-term memory to be encoded in a brain there would need to be some all-but-miraculous effect that caused learned information or sensory experience to be permanently stored as brain states or synapse states, rather like letters being written into clay.  Referring to "the transcriptional signature that encodes a memory in neurons" is rather like saying the words from your lips are a tape  recorder that permanently store what you are saying. But since "transcriptional signatures" bear no resemblance to sensory experience, it's far worse, and would be more like making the double-goofy claim that your heart rate fluctuations are a tape recorder that record all the words you speak. 

We should be extremely suspicious and skeptical whenever scientists suddenly start giving some new answer to a fundamental question,  an answer completely different from the answer they have been dogmatically declaring for years. For example, if scientists were to suddenly start telling us that galaxies are not held together by gravity (as they've been telling us for decades), but by, say, “dark energy pulsations,” we should be extremely skeptical that the new explanation is correct. In this case, there are very good reasons why the speculations in boldface above cannot be right.

Chromatin is a term meaning DNA and surrounding histone protein molecules. Histone molecules are not suitable for storing very long-term memories because they are too short-lived. A scientific paper tells us that the half-life of histones in the brain is only about 223 days, meaning that every 223 days half of the histone molecules will be replaced.

So histone molecules are not a stable platform for storing very long-term memories that can last for 50 years. But what about DNA? The DNA molecule is stable. But there are several reasons why your DNA molecules cannot be storing your memories. The first reason is that your DNA molecules are already used for another purpose – the storing of genetic information used in making proteins. DNA molecules are like a book that already has its pages printed, not a book with empty pages that you can fill. The second reason is that DNA molecules use a bare bones “amino acid” language quite unsuitable for writing all the different types of human memories. The idea that somewhere your DNA has memory of your childhood summer vacations (expressed in an amino-acid language) is laughable.

The third reason is that the DNA of humans has been exhaustively analyzed by various multi-year projects such as the Human Genome Project and the ENCODE project, as well as various companies that specialize in personal analysis of the DNA of individual humans. Despite all of this huge investigation and analysis, no one has found any trace whatsoever of any type of real human memory (long-term or short-term) being stored in DNA. If you do a Google search for “can DNA store memories,” you will see various articles (most of them loosely-worded, speculative and exaggerating) that discuss various genetic effects (such as gene expression) that are not the same as an actual storage of a human memory. Such articles are typically written by people using the word “memories” in a very loose sense, not actually referring to memories in the precise sense of a recollection.

The fourth reason is that there is no known bodily mechanism by which lots of new learned information can be quickly written to the storage area inside a DNA molecule. The fifth reason is that the DNA we see in brain neurons is basically identical to the DNA we see in other parts of the body (such as the DNA from foot cells). If memories were stored in DNA, the DNA in brain neurons would be much different from that of the DNA in other body parts.  We can read DNA (including an epigenome) from dead bodies, and no one has ever found a memory in a dead body. 

It takes about 1 minute for a cell to read only the small part of the DNA needed to make a single protein (and DNA has recipes for thousands of proteins). If your memories were stored in DNA, it would take you hours to remember things that you can actually recall instantly. Thinking that DNA can store your memories is like thinking that your refrigerator can print out your resume. 

The epigenome consists of chemical "marks" on particular parts of DNA that can act to turn off or turn on particular genes. We already know the function of such chemicals (a function different from memory), and no one has any credible theory of how such chemicals could possibly fulfill such a function and also do the infinitely more complex task of storing a memory (which would be something like a functional broom that also lets you fly around like a witch).  Reading and writing such chemical "marks" is a very slow affair, meaning the epigenome can't be the explanation for realities such as the instant recall of a memory or the instant formation of a new permanent memory. 

But couldn't very-long term memories just be stored in some unknown part of a neuron? No, because the proteins that make up neurons have short lifetimes. A scientist explains the timescales:

"Protein half-lives in the cell range from about 2 minutes to about 20 hours, and half-lives of proteins typically are in the 2- to 4-hour time range. Okay, you say, that's fine for proteins, but what about 'stable' things like the plasma membrane and the cytoskeleton? Neuronal membrane phospholipids turn over with half-lives in the minutes-to-hours range as well. The vast majority of actin microfilaments in dendritic spines of hippocampal pyramidal neurons turn over with astonishing rapidity—the average turnover time for an actin microfilament in a dendritic spine is 44 seconds...As a first approximation, the entirety of the functional components of your whole CNS [central nervous system] have been broken down and resynthesized over a 2-month time span. This should scare you. Your apparent stability as an individual is a perceptual illusion."

There is no credible theory of human learned memories could be stored and retrieved by brains. The low-level facts we have learned about the brain reveal it to be an organ with enormous signal noise, unreliable synaptic transmission, billions of synaptic-gap signal slowers, and very high molecular turnover, an organ bearing no resemblance to a system for permanently storing and instantly retrieving memories with high information accuracy.  The fact that the NIH is now betting $1,434,188 on some new theory of neural memory completely different from the memory storage doctrine neuroscientists have been teaching for decades is something that should lead us to suspect cognitive neuroscientists are in disarray, and very much lacking in credibility in their statements about brains and memory.  Similarly, you should have little confidence in some  astronomer if he told you (after twenty years of telling you that star shine is caused by nuclear fusion) that now he has a totally different theory of what causes starlight.

Postscript: The National Science Foundation's query tool shows that $600,000 has been allocated for another bet that synapses don't store memories. That is the amount of money allocated to the project described on this page:

https://www.nsf.gov/awardsearch/showAward?AWD_ID=2050850&HistoricalAwards=false

The project (NSF award # 2050850) is one entitled "Elucidation of RNA-Based Mechanisms of Long-Term Memory Storage." The idea of an RNA-based mechanism of long-term memory storage is an absurd one. RNA is a short-lived molecule. Referring to David Glanzman, the project incorrectly states, " the principal investigator has discovered that long-term memory (LTM) in the marine snail Aplysia appears to be stored in neurons by nuclear changes." No such thing has been discovered by Glanzman or anyone else. Glanzman's paper here received lots of press incorrectly talking about a "memory transfer" between marine snails.  The paper provided no robust evidence for any such thing, and involved study group sizes of only 7, way too small for a reliable result. 

As for NIH Project # 1DP2MH129985-01 discussed on this page, the project has had two years of funding, but it has not produced any papers backing up the idea of memory storage in the epigenome. A search for David Glanzman's recent papers on Google scholar shows that the NSF award # 2050850 has failed to produce any interesting papers backing up claims of RNA-based mechanisms of long-term memory storage.