Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

Abstract

Graphical Abstract Highlights d Single-cell transcriptomes reveal a unique profile of cortical cholinergic neurons d Female-and male-derived cells show distinct neurokineinduced miRNA responses d Differentially enriched microRNA families constitute a selforganizing network d Integrative analysis identifies mir-10/mir-199 regulators of cholinergic function SUMMARYRNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male-and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.

Sex differences: Transcriptional signatures of stress exposure in male and female brains

“…Thanks to these studies, an overview of differences in rodents is slowly building up allowing comparisons with evidence from psychiatric patients to be made. These high-throughput studies include both microarray 123,147 and RNA-sequencing 84,85,[148][149][150][151][152] approaches. Both types of technologies allow for a genome-wide profiling of stress responses in the two sexes and the study of these responses in the context of pathways.…”

Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons

“…Cholinergic networks are notably subject to differences between sexes and changes in mental disease states 27 , but the corresponding structure-function relationships are still unknown.…”

“…Relatively little is known about the morphometry of VChIs, which have been described as sparse, bipolar neurons mostly distributed in cortical layer 2/3 25,26 . Single neuron RNA-sequencing (RNA-seq) analyses have indicated the reactiveness of VChIs to immune-related neurokines 27 . Notably, VChIs were shown to co-release GABA and acetylcholine(ACh), and recent findings highlight their diverse capacities to modulate the activity of neighboring neruons 28,29 .…”

“…Notably, VChIs were shown to co-release GABA and acetylcholine(ACh), and recent findings highlight their diverse capacities to modulate the activity of neighboring neruons 28,29 . Recently, we demonstrated the functional involvement of VChIs in modulating cortical somato-sensory responses in-vivo and showed that they receive direct input from nucleus basalis projection neurons 26 and react to inflammatory signals 27 .…”

Cholino‐ncRNAs modulate sex‐specific‐ and age‐related acetylcholine signals

“…Apart from its regulation of vital functions, ACh is an important effector of the sex-specific, circadian, and age-related variability between individuals [22][23][24][25]. This reflects its capacity to modulate cognitive, behavioral, and immune defense features, and affects human health and well-being in diverse ways.…”