Abstract
Chronic stress precipitates pronounced enhancement of central stress excitability, marked by sensitization of hypothalamic-pituitary-adrenocortical (HPA) axis responses and increased adrenocorticotropic hormone (ACTH) secretagogue biosynthesis in the paraventricular nucleus of the hypothalamus (PVN). Chronic stress-induced enhancement of HPA axis excitability predicts increased excitatory and/or decreased inhibitory innervation of the parvocellular PVN. We tested this hypothesis by evaluating chronic variable stress (CVS)-induced changes in total (synaptophysin), glutamatergic (VGluT2), GABAergic (GAD65), and noradrenergic (DBH) terminal immunoreactivity on PVN parvocellular neurons using immunofluorescence confocal microscopy. CVS increased the total PVN bouton immunoreactivity as well as the number of glutamatergic and noradrenergic immunoreactive boutons in apposition to both the corticotropin-releasing hormone (CRH)-immunoreactive cell bodies and dendrites within the parvocellular PVN. However, the number of GABAergic-immunoreactive boutons in the PVN was unchanged. CVS did not alter CRH median eminence immunoreactivity, indicating that CVS does not enhance CRH storage within the median eminence. Taken together, the data are consistent with a role for both glutamate and norepinephrine in chronic stress enhancement of HPA axis excitability. These changes could lead to an enhanced capacity for excitation in these neurons, contributing to chronic stress-induced hyperreactivity of stress effector systems in the brain.