Prolonged corticosterone exposure induces dendritic spine remodeling and attrition in the rat medial prefrontal cortex

Abstract

The stress-responsive hypothalamo-pituitary-adrenal (HPA) axis plays a central role in promoting adaptations acutely, while adverse effects on physiology and behavior following chronic challenges may result from over-activity of this system. Elevations in glucocorticoids, the end-products of HPA activation, play roles in adaptive and maladaptive processes by targeting cognate receptors throughout neurons in limbic cortical networks to alter synaptic functioning. Since previous work has shown that chronic stress leads to functionally relevant regressive alterations in dendritic spine shape and number in pyramidal neurons in medial prefrontal cortex (mPFC), here we examine the capacity of sustained increases in circulating corticosterone alone to alter dendritic spine morphology and density in this region. Rats were implanted with subcutaneous corticosterone pellets to provide continuous exposure to levels approximating the circadian mean or peak of the steroid for 1, 2, or 3 weeks. Pyramidal neurons in prelimbic area of mPFC were selected for intracellular fluorescent dye-filling, followed by high-resolution 3D imaging and analysis of dendritic arborization and spine morphometry. Two or more weeks of corticosterone exposure decreased dendritic spine volume in mPFC, whereas higher dose exposure of the steroid resulted in apical dendritic retraction and spine loss in the same cell population, with thin spine subtypes showing the greatest degree of attrition. Finally, these structural alterations were noted to persist following a 3-week washout period and corresponding restoration of circadian HPA rhythmicity. These studies suggest that prolonged disruptions in adrenocortical functioning may be sufficient to induce enduring regressive structural and functional alterations in mPFC.

Graphical abstract

Using high-resolution confocal laser-scanning microscopy, the authors show that prolonged elevations in corticosterone induce persistent alterations in dendritic spine morphology and decreased density in rat medial prefrontal cortex. This darkfield image shows layer 2/3 prefrontal pyramidal neurons selected for intracellular dye-filling with Lucifer Yellow (cyan).