The neuroendocrine stress response at single-cell resolution reveals adrenal ABCB1 as key regulator of stress adaptation

Chronic activation and dysregulation of the neuroendocrine stress response has severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. Here, we provide the first unbiased, cell-type-specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal (HPA) axis, under baseline and chronic stress conditions, using single-cell RNA sequencing. Interestingly, the most prominent alterations were observed in the adrenal gland. We identified a population of Abcb1b+ cells involved in stress adaptation in the zona fasciculata of the adrenal. We validated our findings in a mouse stress model and human adrenal tissues from patients with ACTH-dependent Cushing’s syndrome. We demonstrated that transcriptional activity and variants of the ABCB1 gene underlie a dampened HPA axis response, using in-vitro adrenocortical cell lines and functional endocrine testing in depressed patients. Our findings raise the possibility for ABCB1 based stratification of patients with stress-related disorders and modulation of its function as a tailored treatment strategy. Single-cell RNA sequencing characterization of all three components of the HPA axis under baseline (unstressed) and chronic stress conditions.