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 endproducts 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 abstractUsing 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).

Juvenile stress causes reduced locomotor behavior and dendritic spine density in the prefrontal cortex and basolateral amygdala in Sprague–Dawley rats

“…However, some reports suggested that chronic restraint stress in adult rats increases the BDNF mRNA in the BLA (for review see Bennett & Lagopoulos, 2014). In relation to glucocorticoids, several reports have shown that chronic stress causes an increase in glucocorticoid levels in limbic structures such as the PFC and the hippocampus (for review see Bennett & Lagopoulos, 2014;McEwen et al, 1997;McEwen, 2010;Weinstock, 2011. In addition, in the rats, chronic administration of corticosterone causes a retraction of the dendritic tree with a reduced number of dendritic spines in the PFC, hippocampus, and BLA (Anderson et al, 2016;Conrad et al, 2007;Morales-Medina et al, 2009). Consequently, chronic restraint stress resulting in reduced BDNF and increased corticosterone may be responsible for the shrinkage of the dendritic arborization and reduced spinogenesis in the aforementioned regions.…”

Hippocampal brain‐derived neurotrophic factor determines recruitment of anatomically connected networks after stress in diabetic mice

“…Neurons in the PL and ILA express type II glucocorticoid receptors, which have lower affinity for corticosterone and are occupied after stress and during the circadian acrophase (Joëls and Baram, 2009). Chronic stress or protracted administration of exogenous corticosterone reduces dendritic spine density in both regions (Anderson et al, 2016;Goldwater et al, 2009;Radley et al, 2006). Because prelimbic neurons regulate and respond to glucocorticoids, it is possible that the PLA may be an additional node where intrinsic changes contribute to HPA axis disinhibition.…”

The Role of Chronic Stress in Anxious Depression

“…Though it is difficult to correlate the changes in circulating cortisol with clinical findings, 20 in rodent models of chronic stress, there is a decrease in synaptic connections between the mPFC and hippocampus with the paraventricular nucleus of the hypothalamus, as well as a reduction in GRs, 48,49 in response to prolonged exposure to corticosterone. 50 This leads to reactive changes in the excitability of the HPA axis and these upstream regulatory regions (mPFC, hippocampus, and extended amygdala). In contrast, chronic stress also leads to an increase in synaptic density originating within the amygdala, 51 promoting further excitability of the HPA axis.…”