Brain-body communication is a pivotal ability that enables surveillance of body health and well-being, as well as the initiation of movement and control over it. One of the most important features of the brain-body communication is the control over inflammation processes. These take place throughout the entire body in response to pathogen infections (such as Covid-19), to aging or to many diseases. Another crucial type of communication involves internal brain messages. The common element shared by these two communication pathways is that both are controlled by the cholinergic system, initiated by the neurotransmitter acetylcholine. Imbalance of acetylcholine signaling (hereafter referred as the cholinergic “tone”) results in various malfunctional states, from neurodegenerative to cardiac diseases.

In order to sustain a stable cholinergic tone, the body invests huge amounts of energy reflected in the expression of over two dozen different proteins. However, inter-individual variability is vast and modified expression levels of that many proteins could not solely explain it. Therefore, the “immediate suspect” with regard to tremendous phenotypic diversity related to changed cholinergic tone is regulatory elements. Regulatory elements can be short and long nucleic acids (ncRNAs) which do not code for proteins but rather function as controllers of expression preventing enhancing the translation of coding transcripts to their final protein products. 

In this review we demonstrate the complex activity of ncRNAs contributing to variable (yet precise) cholinergic tone between males and females, throughout different ages and even in different organs or daily times in the same human being. We show that different ncRNAs can interact with each-other to form feedback loops that orchestrate inflammatory processes, brain functions, psychological responses and maybe even REM sleep, in a controlled manner that can be limited both in time and space. Lastly, we formed lists of those ncRNAs that we suggest to contribute to cholinergic tone maintenance, and supplied schematic division of them to subgroups according with their phenotypical function.

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