Metabolic status impacts on the emotional brain to induce behavior that maintains energy balance. While hunger suppresses the fear circuitry to promote explorative food-seeking behavior, satiety or obesity may increase fear to prevent unnecessary risk-taking. Here we aimed to unravel which metabolic factors, that transfer information about the acute and the chronic metabolic status, are of primary importance to regulate fear, and to identify their sites of action within fear-related brain regions. We performed a de novo analysis of central and peripheral metabolic factors that can penetrate the blood–brain barrier using genome-wide expression data across the mouse brain from the Allen Brain Atlas (ABA). The central fear circuitry, as defined by subnuclei of the amygdala, the afferent hippocampus, the medial prefrontal cortex and the efferent periaqueductal gray, was enriched with metabolic receptors. Some of their corresponding ligands were known to modulate fear (e.g., estrogen and thyroid hormones) while others had not been associated with fear before (e.g., glucagon, ACTH). Additionally, several of these enriched metabolic receptors were coexpressed with well-described fear-modulating genes (Crh, Crhr1, or Crhr2). Co-expression analysis of monoamine markers and metabolic receptors suggested that monoaminergic nuclei have differential sensitivity to metabolic alterations. Serotonergic neurons expressed a large number of metabolic receptors (e.g., estrogen receptors, fatty acid receptors), suggesting a wide responsivity to metabolic changes. The noradrenergic system seemed to be specifically sensitive to hypocretin/orexin modulation. Taken together, we identified a number of novel metabolic factors (glucagon, ACTH) that have the potential to modulate the fear response. We additionally propose novel cerebral targets for metabolic factors (e.g., thyroid hormones) that modulate fear, but of which the sites of action are (largely) unknown.

Background: Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation, but likely also lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms. Objective: In this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone. Main outcome measures: The efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin embedded hippocampal tissue from the patient and 2 controls. In hippocampal tissue from the patient and 8 controls, mRNA of MR/GR target genes was measured. Results: In vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient. Conclusions: Dexamethasone may induce MR nuclear translocation in human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients.