Stressful and traumatic events can create aversive memories, which are a predisposing factor for anxiety disorders. The amygdala is critical for transforming such stressful events into anxiety, and the recently discovered neuropeptide S transmitter system represents a promising candidate apt to control these interactions. Here we test the hypothesis that neuropeptide S can regulate stress-induced hyperexcitability in the amygdala, and thereby can interact with stress-induced alterations of fear memory. Mice underwent acute immobilization stress (IS), and neuropeptide S and a receptor antagonist were locally injected into the lateral amygdala (LA) during stress exposure. Ten days later, anxiety-like behavior, fear acquisition, fear memory retrieval, and extinction were tested. Furthermore, patch-clamp recordings were performed in amygdala slices prepared ex vivo to identify synaptic substrates of stress-induced alterations in fear responsiveness. (1) IS increased anxiety-like behavior, and enhanced conditioned fear responses during extinction 10 days after stress, (2) neuropeptide S in the amygdala prevented, while an antagonist aggravated, these stress-induced changes of aversive behaviors, (3) excitatory synaptic activity in LA projection neurons was increased on fear conditioning and returned to preconditioning values on fear extinction, and (4) stress resulted in sustained high levels of excitatory synaptic activity during fear extinction, whereas neuropeptide S supported the return of synaptic activity during fear extinction to levels typical of non-stressed animals. Together these results suggest that the neuropeptide S system is capable of interfering with mechanisms in the amygdala that transform stressful events into anxiety and impaired fear extinction.

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.