Astrocyte Bioenergetic Remodeling as a Central Trait of Disrupted Glucocorticoid Signaling: Mechanisms and Implications for Stress Vulnerability.

Glucocorticoids (GCs) are central to the organism's adaptation to stress, coordinating systemic energy distribution and neuroendocrine signaling. While acute effects of GCs are adaptive, chronic GC exposure is increasingly recognized as an important factor contributing to the pathophysiology of neuropsychiatric disorders, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). A piling evidence points to astrocytes as a central integrator of brain response to stress hormones, including GCs. In this review, we discuss a biphasic regulation of astrocyte metabolism by GCs. According to the hypothesis, astrocytes undergo metabolic adaptations in response to GC: acute exposure leads to the enhancement of astrocyte metabolism through upregulation of glycolysis, mitochondrial activation, and glutamate clearance. In turn, prolonged GC exposure induces a metabolic shift toward branched-chain amino acid and lipid catabolism, promoting mitochondrial reactive oxygen species (ROS) production and impairing key homeostatic functions, including the astrocyte-neuron lactate shuttle and calcium signaling. Progressive disruption of astrocytes' supporting function may subsequently lead to synaptic dysregulation and energy imbalance in stress-related brain pathology. We postulate that a detailed understanding of this dynamic regulation is necessary for targeting astrocyte-specific metabolic mechanisms in neuropsychiatric disorders.