Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors

Abstract

Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 g/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

“…Recent animal experiments show that chronic stress results in altered dendritic morphology, and reduced spine density in the mPFC, as has been shown in the hippocampal CA3 region (Cook and Wellman, 2004;Radley et al, 2004Radley et al, , 2006. Treatment with the synthetic glucocorticoid dexamethasone results in neuronal loss and atrophy in the mPFC as well as in the granule cell layer of the dentate gyrus (Cerqueira et al, 2005). In the present study, we extend these findings, and report that chronic social defeat stress can suppress cytogenesis in the mPFC.…”

Rostral Anterior Cingulate Cortex Volume Correlates with Depressed Mood in Normal Healthy Children

“…In line with this hypothesis, a study of ACC volume in adults has shown an inverse correlation with number of stressful or traumatic adverse childhood events (50). There is also a mechanism in place to explain how environmental stressors may alter ACC anatomy; stress induces the release of glucocorticoids, which have been shown to mediate structural alterations of the medial prefrontal cortex (51)(52)(53). It is possible that these structural changes reflect a shift in the activity of neural systems that acts to favor increased vigilance and heightened reactivity to negative emotional stimuli.…”

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

“…The programming effects of stress are most likely mediated by endogenous glucocorticoids (GC) whose ability to produce structural re-organization and dysfunction of the neural substrates that underpin these stress-related pathologies are well known (1,(5)(6)(7). Although administration of prenatal GC does not mimic prenatal stress, synthetic GC such as dexamethasone (DEX) are widely used in obstetrics, e.g.…”