We previously showed that an acute stress (electric footshocks) induced both a rapid plasma corticosterone rise and a reversal of serial memory retrieval pattern in a contextual serial discrimination (CSD) task. This study is aimed at determining (i) if the rapid stress effects on CSD performance are mediated by the hippocampus; (ii) if hippocampal corticosterone membrane receptor activation is involved in the rapid stress effects on CSD performance. In experiment 1, microdialysis in the dorsal hippocampus (dHPC) was used to measure the stress-induced corticosterone rise; in parallel, the effect of acute stress on CSD performance was evaluated. In addition, the functional involvement of corticosterone in the behavioral effects of stress was assessed by administering metyrapone, a corticosterone synthesis inhibitor, before stress. In experiment 2, the involvement of hippocampal corticosterone membrane receptors in the stress-induced reversal of CSD performance was studied by injecting corticosterone-bovine serum albumin (BSA) (a membrane-impermeable complex) in the dHPC in non stressed mice. Results showed that (i) the acute stress induced a rapid (15 min) and transitory (90 min) corticosterone rise into the hippocampus dHPC, and a reversal of serial memory retrieval pattern; (ii) both the endocrinal and memory stress-induced effects were blocked by metyrapone; (iii) corticosterone-BSA injection into the dHPC in non stressed mice mimicked the effects of stress on serial retrieval pattern. Overall, our study is first to show that (i) a rapid stress-induced corticosterone rise into the dHPC transitorily reverses serial memory retrieval pattern and (ii) hippocampal corticosterone membrane receptors activation is involved in the rapid effects of acute stress on serial memory retrieval.

Abstract:The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non sleep-deprived animals. For this purpose, an original sleepdeprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether:First, to evidence that a diurnal 10-hr sleep deprivation period induced an impairment of spatial working memory.Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala).Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-hr sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task.

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The original aims of our study were to investigate the dose-effect relationship of modafinil administration on working memory performance, in parallel with the measurement of plasma corticosterone in chronically-stressed mice, as compared to control mice. Memory performance was evaluated by spontaneous alternation in a T-maze. Vehicle or modafinil (8, 16 or 32 mg/kg) were administered after or without chronic stress (immobilization and exposure to light) for 15 min/day over a period of consecutive 14 days. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels. Under non-stress conditions, corticosterone significantly increased with 16 and 32 mg/kg modafinil administration. Interestingly, optimal working memory performance was revealed at the 16 mg/kg dose. Moreover, no correlation was evidenced between working memory performance and plasma corticosterone level in modafinil-treated animals. Under stress conditions, corticosterone level was lowered at 8 mg/kg and remained unchanged at 16 and 32 mg/kg modafinil. An optimal working memory performance was evidenced at 8 mg/kg, which indicated a decrease in the efficiency threshold of modafinil under stress. Furthermore, an inverse correlation emerged between working memory performance and corticosterone level. Our study evidenced for the first time the interaction between stress and memory, in the emotional modulation of working memory performance, as a function of the administered dose of modafinil.

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