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The biochemistry of the memory storage and processing

Image credit: Images from cottonbro and Rodolfo Clix, downloaded from Pexels and merged.

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JN
J. Nikola Nov 28, 2021
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

Inspiration for the research on memory

As a true Black Mirror fan, I was deeply inspired by the series to do the research on the brain device that helps you to recall memory, called the "grain". You can watch the review to understand it better. What I found on memory formation, storage, and modulation was astonishing.

Applicative examples scratching the surface

A team of researchers from the University of Southern California has created a device to help Alzheimer’s patients recover some of their memory abilities. The device in form of a chip reads the neural activity from the hippocampus of Alzheimer's brain, compares it to the healthy ones, and sends the "healthy" signal back to the brain. In this way, scientists managed to bypass the hippocampus and send the correct signal, thus improving performance in a memory task by 15-25% .
In another study, scientists managed to recreate/transfer memories from one rat's brain into the other, by recording and stimulating neural activity .

Deep dive into the biochemical mechanisms of memory

Introduction to the MeshCODE theory
Recently, I read an interesting paper that provides a new theory on the mechanisms of memory formation, change, and maintenance .
Basically, the author describes a theory that a memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix (ECM) adhesions that organize each and every synapse. The theory is for the first time proposing the exact physical location of data storage in animals, which would also easily function as a read-write memory system, supporting the view of the mind as an organic supercomputer .
The main concepts
The theory is based on the the fact that talin and similar mechanosensitive proteins have 13 domains that can be folded (0) or unfolded (1), and could be considered as "switches". Since talin is the key linkage between the integrin-ECM conncentions and the cytoskeleton, it can, under a certain forces generated by the cytoskeletal components (due to the environmental changes), be folded or unfolded. Many talins of one integrin adhesion can function as the binary Analytical machine, or the so called meshwork of switches (the MeshCODE) .
The "write"
The brain is considered the main calculating and memory machine in animals. It contains 100 trillion synapses, safely isolated inside the soft protective brain tissue. The ECM and integrin adhesion complexes are required for synaptic plasticity, memory formation, long-term potentiation and learning. Since they are protected, synapses can build its own ECM niche, isolate and precisely "translate" mechanical forces to "write" the data into binary talin code .
The "read"
Every synaptic adhesion would alter its signalling as a result of mechanical forces. Following many of these events, neuronal cytoskeleton would precisely contract to generate these mechanical signals and alter the switch patterns. Ligands that engage and stabilise different switch states, such as vinculin, would "read" the data and redistribute accordingly. This way, numerous recognized processes of synaptic regulation could be explained .
The higher level of organization
The high level of brain and, more specifically, cerebral cortex organization suggest the memory could be stored in precisely architectured and layered modules, just like disk drives in computers. Since the MeshCODE could store the data of every synapse, neuron and signalling pathway, it would represent the current state of the organism or - the current machine code the organism is using. It could be the brain's computational power, the memory and the main communication language between the cells. If this proves to be true, it could be the game changer in understanding the memory formation, allocation, changes and consequently, neurological disease/disorder treatment .

The Ask for all the readers

  • What are your thought on the MeshCODE theory?
  • What other proteins could serve the purpose?
  • What proteins could be the main regulators/stabilizers/modificators of the MeshCODE?
  • What experiments could help us prove the theory?
  • How could we record or translate the biochemical binary talin code into the MeshCODE programming language?
  • How would you apply these findings?
Is it coincidence that we developed computing architectures based on binary systems (computers) that share striking similarity with here proposed bichemically binary computational center called the brain?

[1]https://www.abstractsonline.com/pp8/index.html#!/4376/presentation/11106

[2]https://www.frontiersin.org/articles/10.3389/fnsys.2013.00120/full

[3]https://www.frontiersin.org/articles/10.3389/fnmol.2021.592951/full

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Creative contributions

Application: reading the memory of the dead people

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JN
J. Nikola Nov 28, 2021
Either if the crime happened, or we just wanted to know what our loved ones were thinking before their death, we could use the MeshCODE from the hippocampal (temporary; REM) memory storage to "read" recent memories and recreate events that led to death.
Brain REM storage remains active for a few hours after death, while the long-term storage deep in the cortical cortex remains as long as the brain preserves its integrity.
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"Translating" the MeshCODE by fluorescent talins

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JN
J. Nikola Nov 28, 2021
Since the talins have 13 domains that can be folded or unfolded, my idea is to create a talin-dye complex, or the fluorescent genetically-modified talin to visualize the changes in the domain states. I imagine it working similar to pyrosequencing or quenching.
The talin should change the level of fluorescence when the state of each domain changes. Since there are a lot of domains, a new system of reading should be developed.
One way to do it could be to measure the intensity of the total fluorescence. Domains that are unfolded (1) would glow green, and the folded (0) ones would not. That way, we could measure the total number of folded and unfolded domains.
Now we should know the specific arrangement. Since the domains are too close to spatially differ the signals from each other, we could use another fluorescence protein complexed with the talin body with different wavelengths of the fluorescence (e.g. red). That could maybe allow us to calculate the distance of every green signal from the constant red one and extrapolate the binary code. Each talin would be represented as the binary code.
Downloaded from Calderwood et al. and edited.
The problems
  • The distance between the signals could still be too small to differ different regions
  • The sensitivity of the recording system should be enormous
  • The model for testing should be isolated from all environmental forces and present a closed in vitro environment sensitive to only the chosen stimulans.

[1]https://www.nature.com/articles/nrm3624

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Proof-of-concept experiment

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JN
J. Nikola Nov 28, 2021
To make sure the body works perfectly, every MeshCODE should work with high precision and fidelity. Each disruption of folding-refolding, clogging, or structural change of talins could lead to the corrupted code and possibly, a memory loss.
In Alzheimer's disease, abnormal accumulation of tau and amyloid-B has been linked to cognitive decline. Furthermore, amyloid-B has been suggested to play a role in the mechanical integrity of synapses leading to memory loss. A similar process was proposed to play a role in the cognitive decline related to the aging brain .
Therefore, the key thing would be to connect the dots and find out if talin switches can directly or indirectly be disrupted by the accumulation of the above-mentioned proteins and result in memory loss.
I would first do the computational chemistry on the related protein structures and then translate it to in vitro studies.

[1]https://pubmed.ncbi.nlm.nih.gov/9748670/

[2]https://pubmed.ncbi.nlm.nih.gov/25741591/

[3]https://pubmed.ncbi.nlm.nih.gov/23447617/

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Enhancing the memory by diet promoting talin synthesis (experiment)

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JN
J. Nikola Nov 28, 2021
Since talin is suggested to play an important role in processes related to brain memory, its structural integrity is of high importance. It is made of amino acids and is a subject of general protein maintenance. To test the importance of the talin in signal transduction, memory forming, and processing, I suggest a few experiments with the following hypotheses:
  • Older people tend to have lower talin concentrations in the cytosol and the brain synapses
Check general proteomics data in two groups - old and young, and see if there is a pattern of talin expressions, concentrations, genetic modifications, methylations, etc.
**Update: I found a paper that compared concentrations of several proteins in the brains of aged mice. While Tau protein concentrations were increased, ankyrin, talin, spectrin, and actin were differentially decreased.
  • People with dementia or Alzheimer's have lower talin concentrations in the cytosol and the brain synapses
Check general proteomics data in two groups - people with diagnosed dementia and people without dementia of the same age, and see if there is a pattern of talin expressions, concentrations, genetic modifications, methylations, etc.
  • Same-aged rats who were fed with a talin-promoting diet tend to memorize things better
Feed rats with diet that promotes talin synthesis (see which amino acids are the most important and tailor the diet accordingly). Prove the rates that were fed this way have a generally higher talin concentrations, talin to integrin ratio, etc. Check if these rats perform bettor on memory-related tests.
  • Transient talin silencing results in short concurrent memory loss
Use talin siRNA or plasmids to create a transient silencing or permanent talin knockdown. Compare the performance of the knockdown and the control group in memory-related tests.

[1]https://pubmed.ncbi.nlm.nih.gov/7970209/

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General comments

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JN
J. Nikola2 months ago
Here is a paper connecting the actin cytoskeleton and talins. The scientists found out that many proteins (some of which also bind to talin) can modify/shape the F-actin phenotypes with distinct quantitative features. These findings also suggest a conceptual parallel between the actin cytoskeleton and gene regulatory networks, where the talins could play the important role of mediating the signals between the environment and the cell. This goes along with the theory and could also help us to directly determine if the "read" option of the proposed MeshCODE theory would make any sense.
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