Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation

Abstract

Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type–specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of Abcb1b+ cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing’s syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism’s nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.

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

“…Abcd1 -deficient microglia have been correlated with synaptic loss and axonopathy [65] pointing to an Abcd1 -dysregulated network association with synaptic signaling problems. Abcb1 , another member of the ABC transporters family, has been associated with stress adaptation and potential mediation of stress-related psychiatric disorders phenotypes [66]. These findings highlighted that the exclusive analysis of transcriptomic data at the gene-level does not capture all aspects of the transcriptional response to a stimulus, and the DN analysis can unravel distinct but complementary aspects that can lead to specific molecular pathways identification.…”

Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation

“…The fact that Senp2 -deficiency preferentially affects the zF while being expressed in all cortical areas 49 can be explained by two non-mutually exclusive mechanisms. First, the zG already harbours high levels of nuclear SUMOylation compared to the zF 20 , therefore the expected increase in SUMOylation conjugates consecutive to lowered deconjugase pools will preferentially affect hypoSUMOylated regions.…”

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

“…Our findings align with a large body of literature indicating that neuronal dysfunction in the PFC, the central hub of executive functions, contributes importantly to MDD. There are reports from postmortem brain studies from MDD subjects 48, 49 as well as rodent chronic stress models 47, 50, 51 describing the loss of synapses, a decrease in synaptic-related genes, and alterations in mPFC neuronal electrophysiological properties. Similarly, we found that neuronal expression of FEDORA promotes altered expression of synaptic genes along with changes in neuronal excitability.…”