Ketamine Improves the Glymphatic Pathway by Reducing the Pyroptosis of Hippocampal Astrocytes in the Chronic Unpredictable Mild Stress Model – Interesting enough topic to make new post. This is one of the more sensical explanations for the mechanics of ketamine vs. “hard” depression, it aids in flushing the intercellular milieu, allowing new behavioral pathways to be accessed. So if this ends up being consistent, it would suggest that the actual connections between the circuits are far less impactful on “branch choice” than we assume and it’s really all about the chemical stew in the interstitial spaces.
This would result in a pretty dramatic recalculation of our assumptions across the board, instead of thinking about chemicals binding to receptors and the work being done in the cell, think about chemicals causing changes to the intercellular spaces, which modifies the “branches” in real time. Imagine inside of the cell containing the hard data, but the stew between them being the “consciousness”/”ghost”/whatever, separate but intrinsically intertwined.
So the thought that’s really catching me is the idea that interstitial space between the cells works as an active processor of information in and of itself, rather than this being the domain solely of the cells themselves. As an example, it’s not the processing within the neuron or astrocyte specifically that ultimately creates the “decision tree”, but the content of the spaces in between.
Imagine someone taking a “drug” which has fairly dramatic effects on cognition, say getting really drunk. It’s not the cells directly that are being primarily acted upon, it’s the stew that is changing and creating entire new behavior because it is changed.
It kind of reminds me of how quorum sensing output changes the behavior for a group of bacteria, the bacteria change their behavior both to initiate and in response to external soup.
Edit: So like a primary way we’ve been attempting to demonstrate efficacy of certain drugs is by looking at morphology changes, e.g. we give the cluster lots of B6, it got more clustery, thus B6 creates clustery-ing and this is good. In practice, B6 changes the milieu, and the changes to the morphology are induced by the individual’s pre-existing RNA/Protein configuration in response to changes in the milieu.
The long standing question of “why do identical models in as identical conditions as we can think to make them still have different responses” question is entirely down to this, even small changes to the environment can have dramatic changes on the milieu (especially protein expression rates). And it is impossible for any organism to share exactly the same environment as any other one because they do not occupy exactly the same space all the time.
Edit 2: What if inflammation based conditions are an example of the immune<->astrocyte cognitive networks at play, a communication error between them? When we “fix” these, is it either through editing DNA/RNA output (and ultimately the peptide stew) or by modifying the contents of the stew (e.g. NSAIDs), are we adjusting the “communication” between the networks?
The idea that behavior is created outside the cell, rather than inside (or as a function of connections) is really intriguing, and much much more consistent with origin of life theories. I’m taken by how cleanly this scales up to inter-organismal behavior through human sociological constructs.
Edit 3: Wouldn’t it just take the cake if the benefit of exercise was that it shakes up the protein gunk preventing protein accumulation which results in sort of “stuck valves”? Or thinking of calcium waves not as signals to cells specifically, but an attempt to chemically modify/coordinate the mix in the spaces in between? When kids are little you can’t shake your baby, but as they get older, you gotta shake your baby, and eventually things get too fragile to shake your baby.
The assumption that “consciousness”/awareness is a product of cellular recursion (or worse), just gets beat to shit every time it gets tested. What if it’s not about recursion at all, but a complete physiological state which exists in between as part of the metabolic mix?