Charting miRNA regulation across multiple pathways is central to characterizing their role in disease. Yet, current methods expose only isolated miRNA-pathway interactions. We have developed a systems biology approach, Pathway networks of miRNA Regulation (PanomiR) that identifies miRNAs that coordinately target groups of pathways. PanomiR captures activity dynamics of pathways, detects dysregulated pathways, groups pathways by their co-expression, and detects miRNAs that specifically target these coordinated groups of dysregulated pathways. We have used PanomiR to explore disease-associated miRNAs and pathways in liver cancer. We show that it recapitulates known and novel liver cancer pathways, determines their up or down regulation, and sensitively captures biologically meaningful signals independent of detectable differential gene expression. PanomiR organizes liver cancer pathways into three broad groups that reflect pathogenic mechanisms of cancer: activation of transcription, cell cycle and proliferation, and dysregulated signalling. Using either experimentally-supported or predicted miRNA-mRNA interactions, PanomiR robustly detects and identifies miRNAs central to liver cancer, unbiased by the number of their gene targets-making it possible to place these cancer miRNAs using PanomiR into the context of co-activated pathways that they regulate. PanomiR is a sensitive, unbiased framework for detection of disease-specific multi-pathway programs under miRNA regulation. PanomiR is accessible as an open-source R/Bioconductor package: <https://bioconductor.org/packages/PanomiR>.

The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.