Attenuating corticosterone levels on the day of memory assessment prevents chronic stress‐induced impairments in spatial memory

Abstract

This study investigated whether chronic stress-induced spatial memory deficits were caused by changes in the hypothalamic-pituitary-adrenal axis, such as corticosterone (CORT) elevations on the day of memory assessment, rather than the consequence of structural changes in the hippocampus. Male Sprague-Dawley rats were restrained for 6 h/day/21 days, and spatial memory was assessed on the Y-maze on day 22. Ninety minutes before training, rats received a subcutaneous injection of vehicle or metyrapone, a CORT synthesis inhibitor, and then spatial memory was determined 4-h later. The highest dose of metyrapone (75 mg/kg, s.c.) was most effective at preventing stress-induced spatial memory deficits. Chronic stress increased total CORT levels following Y-maze exposure, while acute metyrapone treatment dose-dependently attenuated total and free (unbound) CORT levels in both stress and control conditions. Blood samples taken from a separate subset of chronically stressed rats showed that baseline CORT levels were similar across the restraint period. Finally, chronic stress down-regulated glucocorticoid, but not mineralocorticoid, receptor mRNA expression within the hippocampus (dentate gyrus, CA1, CA2, CA3). These findings suggest that chronic stressinduced spatial memory deficits may be mediated by hypothalamic-pituitary-adrenal axis dysregulation. Specifically, CORT elevations and reductions in hippocampal glucocorticoid receptor expression, at the time of behavioural assessment may be involved, as opposed to a direct effect that is solely dependent upon hippocampal structural changes. These results have significance for treating cognitive decline in conditions associated with elevated glucocorticoids that include subpopulations in ageing, depression, Cushing's disease and Alzheimer's disease.

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

“…It is well-established that chronic exposure to high levels of corticosterone is detrimental for learning and synaptic plasticity in non-diabetic animals [24][25][26][27][28][29] . The corticosterone-mediated adverse effects of diabetes were not determined by changes in insulin production, because they occurred in db/db mice with elevated insulin levels, and in insulin-deficient rats.…”

“…Enhancement of hippocampal function by normalizing corticosterone levels in diabetic animals was completely reversed by administration of high levels of corticosterone, demonstrating that corticosterone (rather than some other adrenal-derived factor) was responsible for the adverse effects of diabetes on hippocampal plasticity. These findings strongly support a role for elevated corticosterone levels in impaired hippocampal plasticity and cognition induced by diabetes.It is well-established that chronic exposure to high levels of corticosterone is detrimental for learning and synaptic plasticity in non-diabetic animals [24][25][26][27][28][29] . The corticosterone-mediated adverse effects of diabetes were not determined by changes in insulin production, because they occurred in db/db mice with elevated insulin levels, and in insulin-deficient rats.…”

“…Although it is not known whether glucocorticoids are involved in cognitive dysfunction in diabetes, elevated cortisol levels have been associated with poor cognitive ability in humans subjected to psychosocial stress 21 , during normal aging 22 and in Alzheimer's disease 23 . Studies of rodents have provided evidence that elevated adrenal glucocorticoids mediate deficits in cognitive function caused by chronic stress 24,25 . In addition, chronic stress and high levels of corticosterone can impair synaptic plasticity [26][27][28][29] .…”

The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms

“…First, individual rat strains have unique profiles in response to stress (Herman et al, 1999) and extrapolating findings from one strain in order to apply them to another should be performed with caution. In the current study, we used Sprague-Dawley rats, which are commonly used with 6h/21d restraint (Beck and Luine, 2002;Conrad et al, 1996;Pham et al, 2003;Wood et al, 2003;Wright et al, 2006). In contrast, Vyas et al (2002) used Wistar rats, which are commonly used in unpredictable stress protocols and shorter restraint/ immobilization paradigms (Gerrits et al, 2003;Marin et al, 2007;Mitra et al, 2005;Mizoguchi et al, 2001;Sousa et al, 2000;Vyas et al, 2002;Vyas and Chattarji, 2004).…”

“…While some reports demonstrate that chronic stress impairs motivation (Mizoguchi et al, 2002), including studies using chronic restraint for 6h/21d (Kleen et al, 2006), most chronically stressed rats tested on the Y-maze show motivation to explore (Conrad et al, 1996;Wright and Conrad, 2005;Wright et al, 2006). One of the advantages of using the Ymaze is that motivation is dependent on a rat's innate interest in novelty seeking, and food restriction is not needed to motivate rats to perform (for review see Conrad, 2006).…”