Homeostasis to Allostasis: Prefrontal Astrocyte Roles in Cognitive Flexibility and Stress Biology

In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.