On a lower level, the brain has two hierarchies of synapses: a top-down processing hierarchy, driven by the neurochemical AMPA, and the bottom-up processing hierarchy, driven by the neurochemical NMDA. These hierarchies have salience passed back and forth between them by dopaminergic and adrenergic signalling from other brain regions. Whichever side of processing is "dominant" at the time, is training its dual to respond with the signals the active side is receiving, in response to the signals the active side is sending. Additionally, the bottom-up processing hierarchy is wired to your senses and your motor neurons.

In short, the top-down processing hierarchy is "the model", and the bottom-up processing hierarchy is "the evidence." The brain switches between using the evidence to train the model (when the evidence is salient and the model is weak), and using the model to predict and "fill in for" the evidence (when the model is salient and the evidence is noisy.)

It would make a lot of sense to me if psychosis were simply a result of chronically overdriven AMPA signalling, such that evidence is always being "fit to" the existing model, with the bottom-up hierarchy never being granted enough dominance to use the evidence to correct the model.

This is fascinating. I grew up with a schizophrenic parent and relatives. My interpretation has been that the disease is a defect in the systems that weights between internal models and external evidence.

It’s interesting that to know that there might be a fairly straight forward mapping of the to brain chemistry/neural mechanisms.

Do you any references the AMPA signaling pathways and associated neurological structures that you can recommend as a starting point?

Ah interesting. I didn't realize we'd categorized such a hierarchy. Reminds me of something Hoftstadter wrote in one of his earlier books.

I saw schizophrenia described by a person with it as "dreaming while you're wide awake". In a dream, your brain jumps on any details to invent more details to continue the dream. In a dream, if your brain says the dry cleaners are a shady government organization, then that's a valid and successful continuation of the dream, and dream reality bends to that. In waking reality, not so much.

NMDA antagonists usually make it possible to dream while awake. Low NMDA goes with higher dopamine and higher NMDA with norepinephrine. Schizophrenia is said to be associated with poor NMDA signaling (high agmatine, low D-serine/coagonists, high NMDA receptor antibodies, etc).

I've been wondering about dopamine for a while. I seem to have symptoms of both too much and too little dopamine, simultaneously.