Let us look at a science paper attempting to convince us that memories are stored in synapses. The 2018 paper by Wayne S. Sossin is entitled "Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal." You should take careful note of the phrase "a proposal" at the end. It indicates the speculative nature of what Sossin writes about. To make a proposal about some possibility typically does not have a hundredth of the worth of making an observation showing the likelihood of such a possibility.
The abstract of the paper incorrectly states "there are strong evidential and theoretical reasons for believing that memories are stored at synapses." No such reasons exist, but there are very strong reasons for rejecting such a claim, such as the very short lifetimes of the proteins that make up synapses (less than two weeks), and the instability of the dendritic spines such synapses are attached to. The body of the paper begins by stating, "Most neuroscientists believe that memories are encoded by changing the strength of synaptic connections between neurons (Mayford et al., 2012; Poo et al., 2016)." The two references do not take us to any papers showing that most neuroscientists believe such claims about synapses. It merely takes us to two papers in which a few neuroscientists seem to speak as if they support such claims.
The claim that most neuroscientists believe such a thing about synapses is a common claim, but it is never well-supported. How could you substantiate such a claim, which is not a claim about synapses themselves, but instead a claim that most neuroscientists believe some particular thing about synapses? The only way you could do that is by referring to an opinion poll taken of neuroscientists, one that showed that a majority of them believed that memories are stored in synapses. For the opinion poll to be persuasive, it would have to be a secret ballot poll. Any kind of "show of hands" claim would not be persuasive, because there are sociological reasons and psychological reasons why scientists might prefer to publicly act like they are going along with some majority, rather than publicly defying such a majority. But secret ballot polls of neuroscientists virtually never are done. We have no actual evidence that a majority of neuroscientists believe that memories are stored in synapses. We merely have quite a few neuroscience papers in which authors claim that most neuroscientists believe such a thing. Even if it were true that most neuroscientists believe that memories are stored in synapses, that would not show the likelihood of such a thing. There are all kinds of sociological and groupthink and "follow the herd" reasons why an erring belief tradition about synapses might arise in the neuroscientist community.
The second sentence of the body of the paper makes a misleading claim: "The great success of deep learning systems based on units connected by modifiable synaptic weights has greatly increased the confidence that this type of computational structure is a powerful paradigm for learning." So-called "neural nets" do not use any arrangement matching an arrangement of matter in the brain, and never should have been called "neural nets." The parts of a neural net that are sometimes called "synaptic weights" but mainly just called "nodes" or "weights" are stable electronic units or software variables that bear no resemblance to unstable non-electronic synapses in the brain. Computerized "deep learning" systems do nothing to substantiate the idea that synapses store memories.
Without trying to summarize the reasoning of the paper, I can give you a taste of how speculative it is by simply quoting statements in it that use the words "may," "could" or "might":
"The selection of a neuron to participate in a memory may also leave long-lasting transcriptional marks such as changes in histone and DNA methylation, and long-term changes in the organization of the nucleus....If transcription were also required for the maintenance of memory, it would suggest that a form of synaptic tagging may also be important for the maintenance of memory. However, in synaptic tagging the half-life of the tag has been measured to be at most a few hours (Martin et al., 1997; Frey and Morris, 1998b), whereas the half-life of the tag would need to be much longer for it to play a role in the maintenance of memory....Conformational changes induced by the priming phosphorylations may also be important in maintaining binding interactions important for localization of the PKMs and may be important for the ability of these reagents to work as isoform-specific dominant negatives....A model for a positive feedback loop of phosphorylation has been proposed...Compensation for the loss of PKMζ may be due to cleavage of PKCι to PKMι by calpains, although this is purely speculative at present.... Increasing AMPA receptor endocytosis may play a role in active forgetting.... Inhibition of BRAG2 may be a target of persistent kinase phosphorylation (Sacktor, 2011). However, since many forms of LTD require BRAG2 (Scholz et al., 2010), the specific removal of AMPA receptor complexes at memory synapses may also require distinct motifs or adaptors that are regulated by persistent kinase activity in addition to BRAG2....Connection between two neurons may consist of a stable component and a memory component. Removal of either component may be sufficient to reduce synaptic strength and thus compromise memories that depend on this increase in synaptic strength....Memory synapses or memory modules at synapses may be defined through specific trans-synaptic adhesive interactions that align the AMPA receptor complexes specific for memory with specific presynaptic molecular complexes. These presynaptic molecular complexes may also have specializations important for memory...There may be multiple adhesion pairs that define distinct types of memory synapses or memory modules at synapses. One can envision trans-synaptic adhesion as defining what is often referred to in the plasticity literature as a “slot.”...An appealing model would be that as well as causing endocytosis of the AMPA receptors, the 'slot' proteins would also be a target of endocytosis after inhibition of the persistent protein kinase....The concept of a memory synapse remains an unproven hypothesis. Generating a memory synapse may require multiple rounds of modifications...Both pre-and postsynaptic gene expression may be required to generate specific adhesion proteins that attract specific AMPA receptor complexes and presynaptic specializations,
We also have these statements:
"The dominant negative PKMs could distinguish molecular complexes involved in associative and non-associative LTF, interfering specifically at synapses with one type of complex but not the other,.. Inhibition of persistent kinases in the presynaptic cell could also lead to endocytosis of the presynaptic partner of the adhesion complex."
This speculative gobbledygook does not at all add up to a real theory of how synapses could store memories. All that we have here is some jargon making noises that may sound like an explanation to some people. A real theory of synaptic memory storage would give us specific hypothetical examples describing precisely how some specific learned information (such as the statement "my dog has fleas") could be stored in synapses. We never get such specifics from synaptic memory theorists. We basically get just jargon-laden hand waving, often decorated with poorly documented equations designed to impress us.
A 2019 paper gives us another example of wobbly hand-waving guesswork. We read this:
"A signal complex like CaMKII/Tiam1 is proposed as a molecular memory... CaMKII may also act as an activity-dependent scaffold to assemble proteins at the synapse in addition to F-actin binding through CaMKIIβ....CaMKIIβ may play a structural role in targeting the RAKECs of CaMKII in the synapses via actin...These knock-in CaMKIIα molecules may have a dominant negative effect to form RAKECs in the synapses...These kinases may form a RAKEC with their specific substrates or upstream kinases....The RAKEC may be a general mechanism for the maintenance of the biochemical activity of kinase and its substrate...Synaptic localization of βPIX may also be regulated by LLPS."
Then we have in the same paper these uses of the word "could"
"Actived [sic] CaMKII could be diluted by inactive CaMKII from the cytosol....Upregulation of the CaMKIIα protein after LTP could further dilute activated CaMKIIα...The regulation of F-actin could be a candidate for LTP maintenance....CaMKII could act as an activity-dependent scaffold for assembling signaling proteins in the synapse...The interaction of CaMKII with synaptic proteins, including NMDAR, could be phase-separated from other synaptic proteins...The RAKEC between Tiam1 and CaMKII may serve not only as signal machinery to maintain Rac1 activity but could also form the LLPS, in which many synaptic signaling proteins are assembled together or are put on standby to act efficiently and effectively to maintain LTP for longer periods."
A diagram in the paper has a circle with "CAMKII" inside it, surrounded by eight text boxes, five of which have a question mark at the end. I cannot recall ever seeing so many question marks in a scientific diagram. At the bottom of the diagram we see an arrow pointing to the words "memory maintenance," which hardly makes sense given that the average lifetime of a CAMKII protein molecule is a mere 30 hours (according to the paper here).
There is a reason why both papers quoted above are unsubstantial. You cannot have a substantial theory of the long-term preservation of memories in the human brain (with memories being preserved for decades) unless you first have a detailed theory of how human learned knowledge could be represented in a brain. Neither of these papers advance any such theory or endorse any such theory. There simply does not exist a detailed theory of how the many diverse forms of human learned knowledge and human experience could be represented in a brain. If you don't have such a theory, any set of speculations about "memory maintenance" or the lifelong preservation of memories in a brain is a "castle on a cloud" affair rather like a penthouse apartment without any apartment building underneath it.
One of the papers above makes a speculative appeal to a "feedback loop." Appeals to the possibility of such "feedback loops" appear often in the speculative papers of brain memory theorists. Such appeals are sterile and futile, being based on the erroneous simplistic nonsense that "synapse strengthening" can explain memory. To explain a physical storage of human experiences and learned information, you would need some incredibly complicated and multifaceted system (unlike any yet discovered in the brain) that would need to be a billion times too complex to be centered around mere strengthening. Having foolishly got in bed with the vacuous notion that memories can be explained by some mere strengthening, our synapse theorists then think that they can account for the gigantic discrepancy between the short lifetimes of synapses and their dendritic spines and the short lifetimes of synapse proteins, by speculating about "feedback loops" that might preserve the strength of some synapse. But since the whole original idea that a mere strength level could store a memory was very foolish, this appeal to never-discovered "feedback loops" preserving synapse strength is equally foolish. Similarly, thinking that information can be stored in clouds is foolish, so thinking that information could be preserved in clouds long-term through "cloud-to-cloud information transfer" is an idea that is futile and sterile.
In the papers presenting such speculations, we typically see a simple-looking diagram mentioning a feedback loop. The diagram below gives you a better idea of the kind of thing that would have to be going on for "feedback loops" to be preserving information in unstable synapses. Every little token of information would need to have its own special "feedback loop" to preserve that particular type of information. So the stable storage of as simple a piece of information as "my dog has fleas" in unstable synapses would require many types of feedback loops, as shown in the diagram below:
You may realize how utterly nonsensical it is to imagine such a thing when you realize that the chemical units imagined to implement these feedback loops would be short-lived chemicals, and that synapses are attached to dendritic spines that do not last for years, and often don't even last for six months. So such "feedback loops" would themselves be very unstable, and could never account for stable memories that last for decades.
One of the papers quoted above speculates that CAMKII might be the key to some miracle of "memory maintenance" by which memories last for decades while stored in synapses that don't last for years, built of proteins that last for less than two weeks. Contrary to such speculations, a 2019 paper states, "Overall, the studies reviewed here argue against, but do not completely rule out, a role for persistently self-sustaining CaMKII activity in maintaining LTP and LTM [long-term memory]." A speculative appeal has also been made to the idea that a protein PKCζ might help cause such a miracle of memory maintenance, but a paper says that "LTP and memory are retained in PKCζ knockout mice," referring to mice genetically modified to have no such PKCζ. The paper tells us, " In the strongest sense of ‘necessity’ for LTP/memory maintenance, therefore, neither CaMKII nor PKMζ meets the criterion."
The papers quoted above were from a 2018 paper and 2019 paper, and in 2023 we still have nothing more weighty to substantiate claims that memories are stored in synapses. A 2022 paper makes this confession:
"We are still far from identifying the 'double helix' of memory—if one even exists. We do not have a clear idea of how long-term, specific information may be stored in the brain, into separate engrams that can be reactivated when relevant."
Another 2022 paper makes this confession: "How the brain stores and retrieves memories is an important unsolved problem in neuroscience."
Postscript: A 2022 paper has the very unjustified title "CaMKII: a central molecular organizer of synaptic plasticity, learning and memory." No robust evidence is produced for such claims, and we mainly have lots of uses of "may," "might," "perhaps" and "could."
For example, here are the paper's uses of "may":
"CaMKII may exist in distinct populations in dendritic spines....CaMKII may serve as a ‘sponge’ to sequester various postsynaptic proteins, thereby triggering Ca2+-dependent trafficking of various proteins...Phosphorylation of SHANK3 by CaMKII may play a part here...This pool may represent cytosolic, unbound CaMKII molecules.... The interaction of CaMKIIα with α-actinin may also contribute to its interaction with F-actin...Reciprocal activation within a kinase–effector complex may be a general mechanism to maintain local CaMKII signalling for an extended period...This so-called inverse tagging of non-stimulated spines with ARC may increase the contrast of synaptic weights...CaV1.2-mediated influx may be sufficient to enable temporary activation of CaMKII...CaMKII may mediate LTP partly by phosphorylating TARPs...NMDAR-mediated calcium influx may make TARPs more accessible for CaMKII,...RHOA activation in response to glutamate uncaging may require other calcium-dependent processes in addition to CaMKII, which may indirectly regulate RHOA...RHOA may destabilize spines so that they can undergo structural changes during synaptic plasticity...Calcium signalling may be inhibited by CaMKII activation."
Here is where the paper uses the word "might":
"The CaMKII pools in spines that mediate these effects might be small and functionally defined by prolonged interactions of CaMKII with its various binding partners that enable them to contribute to the maintenance of basal transmission and long-term memory...There might be about 100-fold more CaMKII molecules in spines than GluN2B... LLPS of CaMKII might mediate not only the accumulation of CaMKII beneath the synaptic contact but also the formation of glutamate receptor nanodomains at the surface...That α-actinin also binds CaMKII might be important for the CaMKII mediated phosphorylation of S73 of PSD95...This might impair the inhibitory activity of the other helix in the dimer in trans, and thus facilitate substrate binding...CaMKII might need to maintain its own phosphorylation of T286 for continued interactions with other postsynaptic proteins... Synapses in a knockout neuron could be at a collective disadvantage and ‘lose out’ to other synapses formed nearby that might become stronger because resources of the presynaptic input neurons might be allocated to the synapses that they form with surrounding neurons....NMDAR-anchored CaMKII might phosphorylate nearby AMPARs that then become trapped when diffusing through AMPAR nanodomains...S831 phosphorylation augments single-channel conductance of AMPARs134,135, which might contribute to an increase in postsynaptic response during LTP induction."
Here is where the paper uses the word "could":
"It could be explained by an additional phosphorylation state or association with other proteins that protect CaMKII from phosphatase action..... These changes could occur at the sites of pre-existing CaMKII–SHANK3 complexes or could induce a redistribution of CaMKII from the spine interior to the PSD...Binding could provide a pool of CaMKII inside spines that can relocate moderately quickly during early phases of LTP... The kinase could be fully activated by Ca2+–CaM, resulting in increased EPSC amplitude....Other sources of calcium could drive CaMKII activation under basal, non-stimulated conditions to augment synaptic strength...This requirement for catalytic activity to increase AMPAR-mediated currents could reflect the need to phosphorylate other substrates... This increase in postsynaptic response could be mediated by recruitment of GluA1 homomeric AMPARs....A lasting increase in postsynaptic AMPAR function could be through phosphorylation of the auxiliary AMPAR subunit TARPγ2...That TTPL is not required for (non-fusion) TARPγ8 to localize AMPARs153 could be explained by a second, electrostatic interaction site between TARPs and the first PDZ of PSD95.... The phosphorylation of T305 and T306 reduces CaMKII–NMDAR binding157 and increases autonomous CaMKII activity, which could especially apply to phosphorylation sites in CaMKII target proteins that are important for LTD.'
Here is where the paper uses the words "hypothesized," "postulate," "perhaps" or "proposed":
"We postulate that the LLPS of CaMKII has two key roles in synaptic plasticity....It has been proposed that CaMKII acts to a large degree as an activity-dependent structural protein... The GluN2B–CaMKII interaction has been hypothesized to occur in a binding pocket different from the substrate-binding pocket...Such protein–protein interactions have been proposed to provide another mechanism for molecular memory during LTP....Early studies proposed that calcium–calmodulin (CaM)-dependent kinase II (CaMKII) has two discrete binding sites:....Most of this integration over seconds is perhaps due to the autonomous activity of CaMKII...Perhaps under basal neuronal-activity conditions, NMDAR-mediated calcium influx is more effective than CaV1.2-mediated influx in stimulating T305/T306 phosphorylation and thus preventing an increase in AMPAR activity....Perhaps CaMKII facilitates synaptic strengthening through trans-synaptic mechanisms...Perhaps the C terminus of GluA1-fused TARPγ8 has a higher propensity than the free TARPγ8 to detach from the plasma membrane and thus to bind to PSD95, independent of its CaMKII-mediated phosphorylation."
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