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Marthe Vogt Lecture

Pursuing RNA regulators of coding transcripts ensuring balanced acetylcholine (ACh) functioning in health and disease revealed immense complexity in the cholinergic network and its changes under acute stress and nervous system diseases. The 3′terminal regions in mRNAs respond to microRNAs (miRNAs) that interact with complementary recognition motifs of 7– 8 nucleotides that enable suppression of those mRNAs and operate as flags. These short flags often exist in many coding mRNAs whose protein products together constitute entire biological networks, namely, one miRNA can often block many members of a specific pathway. The miRNAs targeting the acetylcholinerelated genes, “CholinomiRs” such as miR132 may block inflammation, impose metabolic impact, and regulate neuronal functioning. However, recruiting CholinomiRs to solve a crisis situation may be too slow when blood cells urgently need to rebalance immune system activation to face this crisis, avoid brain penetration and prevent excessive inflammatory reactions. A “changing of the guards” process enables a solution, where blood cells CholinomiRs decline and cholinergictargeted transfer RNA (tRNA) fragments (CholinotRFs) increase. Since tRNAs bring amino acids to the growing protein chains, they exist in all cells. Cutting each tRNA into pieces would only require a nuclease, and the fragments may rapidly operate like miRNAs. That noncoding regions bind to small RNA regulators further predicts diverse reactions to stressful events, individual heterogeneity in neurodegenerative diseases and new indications for disease prevention. Striking differences in the cortical miRNAs targeting cholinergic transcripts between men and women with schizophrenia and bipolar disorder reflects global differences in responses to therapeutics between men and women with mental and other diseases. The mRNA profiles should hence be viewed as a glimpse into a complex picture, which is consistently subjected to dynamic regulation in health and disease, in a sexand agerelated manner.