DiffBrainNet: differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions

Abstract

Genome-wide gene expression analyses are invaluable tools for increasing our knowledge of biological and disease processes, allowing a hypothesis-free comparison of gene expression profiles across experimental groups, tissues and cell types. Traditionally, transcriptomic data analysis has focused on gene-level effects found by differential expression. In recent years, network analysis has emerged as an important additional level of investigation, providing information on molecular connectivity, especially for diseases associated with a large number of linked effects of smaller magnitude, like neuropsychiatric disorders and their risk factors, including stress. In this manuscript, we describe how combined differential expression and prior-knowledge-based differential network analysis can be used to explore complex datasets. As an example, we analyze the transcriptional responses following administration of the glucocorticoid/stress hormone receptor agonist dexamethasone in C57Bl/6 mice, in 8 brain regions important for stress processing: the prefrontal cortex, the amygdala, the paraventricular nucleus of the hypothalamus, the cerebellar cortex, and sub regions of the hippocampus: the dorsal and ventral Cornu Ammonis 1, the dorsal and ventral dentate gyrus. By applying a combination of differential network- and differential expression-analyses, we find that these explain distinct but complementary aspects and biological mechanisms of the responses to the stimulus. In addition, network analysis identifies new differentially connected partners of important genes and can be used to generate hypotheses on specific molecular pathways affected. With this work, we provide an analysis framework and a publicly available resource for the study of the transcriptional landscape of the mouse brain: DiffBrainNet (http://diffbrainnet.psych.mpg.de), which can identify molecular pathways important for basic functioning and response to glucocorticoids in a brain-region specific manner.

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

“…This suggests that other stress-induced signals can also regulate these genes more slowly or with a greater delay. Indeed, a recent study reported that activation of the glucocorticoid receptor by dexamethasone can induce strong transcriptomic changes 4 hours after injection across multiple brain regions (Gerstner et al 2022) . Analyzing their data we found that Dio2 , Ppp1r3c and Ppp1r3g were all upregulated 4 hours after dexamethasone injection.…”

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

“…This suggests that other stress-induced signals can also regulate these genes more slowly or with a greater delay. Indeed, a recent study reported that activation of the glucocorticoid receptor by dexamethasone can induce strong transcriptomic changes 4 hr after injection across multiple brain regions ( Gerstner et al, 2022 ). Analyzing their data we found that Dio2 , Ppp1r3c, and Ppp1r3g were all upregulated 4 hr after dexamethasone injection.…”