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Summary Aim Although cognitive deficits commonly co‐occur with stress‐related emotional disorders, effect of procognitive drugs such as histaminergic H3 receptor antagonists are scarcely studied on memory retrieval in stress condition. Methods Experiment 1. Memory of two successive spatial discriminations (D1 then D2) 24 hours after learning was studied in a four‐hole board in mice. H3 receptor antagonist ciproxifan (ip 3 mg/kg) and acute stress (three electric footshocks; 0.9 mA; 15 ms) were administered 30 and 15 minutes respectively before memory retrieval test. Fos immunostaining was performed to evaluate the neural activity of several brain areas. Experiment 2. Effects of ciproxifan and acute stress were evaluated on anxiety‐like behavior in the elevated plus maze and glucocorticoid activity using plasma corticosterone assay. Results Experiment 1. Ciproxifan increased memory retrieval of D2 in nonstress condition and of D1 in stress one. Ciproxifan mitigated the stress‐induced increase of Fos expression in the prelimbic and infralimbic cortex, the central and basolateral amygdala and the CA1 of dorsal hippocampus. Experiment 2. Ciproxifan dampened the stress‐induced anxiety‐like behavior and plasma corticosterone increase. Conclusion Ciproxifan improved contextual memory retrieval both in stress and nonstress conditions without exacerbating behavioral and endocrine responses to stress. Overall, these data suggest potential usefulness of H3 receptor antagonists as cognitive enhancer both in nonstress and stress conditions.

International audience; Adult mice emit many ultrasonic vocalizations (USVs) during social interaction tasks, but only a few studies have yet reported USVs in stressed adult mice. Our aim was to study which experimental conditions favor USV emission during behaviors associated with different emotional states. As USVs likely mediate social communication, we hypothesized that temporary social isolation followed by exposure to a novel social congener would promote USV emission. USVs were recorded in three different behavioral paradigms: restraint, free moving in a new environment, and during a social interaction task. We compared USV emission, with or without the presence of a social congener, in animals socially isolated during different periods (0, 6 or 21 days). Social isolation decreased the number of USVs during free moving, whereas it increased during restraint. During the social interaction task, animals produced high-frequency USVs (median: 72.6 kHz, 25-75% range: 67.6-78.2 kHz), especially when the social partner was active and social motivation was high. During restraint, presence of a social congener increased the call rate of low-frequency USVs (median: 52.4 kHz, 25-75% range: 44.8-56.5 kHz). USV frequency followed two unimodal distributions that distinguished low-frequency USVs (≤ 60 kHz) mainly emitted during free-moving (90.9% of total USVs) and restraint (93.1%) conditions, from high-frequency USVs (> 60 kHz) mainly emitted during the social interaction task (85.1% of total USVs). The present study confirms that USV call rate and frequency depend on behavioral states, and provides evidence that the presence of a congener promotes ultrasonic vocalizations in restrained adult mice.

STUDY OBJECTIVES: The regulation of sleep-wake cycles is crucial for the brain's health and cognitive skills. Among the various substances known to control behavioral states, intraventricular injection of neuropeptide S (NPS) has already been shown to promote wakefulness. However, the NPS signaling pathway remains elusive. In this study, we characterized the effects of NPS in the ventrolateral preoptic nucleus (VLPO) of the hypothalamus, one of the major brain structures regulating non-rapid eye movement (NREM) sleep. METHODS: We combined polysomnographic recordings, vascular reactivity, and patch-clamp recordings in mice VLPO to determine the NPS mode of action. RESULTS: We demonstrated that a local infusion of NPS bilaterally into the anterior hypothalamus (which includes the VLPO) significantly increases awakening and specifically decreases NREM sleep. Furthermore, we established that NPS application on acute brain slices induces strong and reversible tetrodotoxin (TTX)-sensitive constriction of blood vessels in the VLPO. This effect strongly suggests that the local neuronal network is downregulated in the presence of NPS. At the cellular level, we revealed by electrophysiological recordings and in situ hybridization that NPSR mRNAs are only expressed by non-Gal local GABAergic neurons, which are depolarized by the application of NPS. Simultaneously, we showed that NPS hyperpolarizes sleep-promoting neurons, which is associated with an increased frequency in their spontaneous IPSC inputs. CONCLUSION: Altogether, our data reveal that NPS controls local neuronal activity in the VLPO. Following the depolarization of local GABAergic neurons, NPS indirectly provokes feed-forward inhibition onto sleep-promoting neurons, which translates into a decrease in NREM sleep to favor arousal., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; Mice emit ultrasonic vocalizations (USVs) in various interaction contexts in adulthood and infancy. One of the essential current questions about mouse USVs is to understand their precise biological significance and roles during social behaviors. Multiple data demonstrate that mouse USVs might be emitted during positive or negative animal states with specific acoustic features, suggesting a role as biomarkers of the animal emotional state. Other experiments demonstrated that male mouse dyads and female mouse dyads essentially vocalize only during contacts. These results advocate for a role of USVs as a vehicle conveying information within a social communication system. USVs could serve as signals indicating a particular emotional state of the sender to the individuals in the vicinity. We review in this chapter how USV studies help in better characterization and validation of mouse models in various pathological conditions with emotional state and social cognition alterations. We will confront data from several models of psychiatric disorders involving social deficits, namely autism, schizophrenia, and stress-related disorders.

Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders. However, few works have tried to identify their cognitive effects after sleep restriction and their impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction in a shaker apparatus that prevents sleep by transient (20-40 ms) up and down movements. Number of stimulations (2-4), and delay between 2 stimulations (100-200 ms) were randomized. Each sequence of stimulation was also randomly administered (10-30 s interval) for 20 consecutive hours during light (8 h) and dark (12 h) phases. Immediately after 20 h-sleep restriction, mice were injected with H3 antagonist (ciproxifan 3 mg/kg ip) and submitted 30-min later to a working memory (WM) task using spatial spontaneous alternation behaviour. After behavioural testing, brains were perfused for Fos immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8±1.4% to 9.2±2.7%, p

International audience; Sleep restriction (SR) impairs short term memory (STM) that might be related to different processes. Neuropeptide S (NPS), an endogenous neuropeptide that improves short term memory, activates arousal and decreases anxiety is likely to counteract the SR-induced impairment of STM. The objective of the present study was to find common cerebral pathways in sleep restriction and NPS action in order to ultimately antagonize SR effect on memory. The STM was assessed using a spontaneous spatial alternation task in a T-maze. C57-Bl/6J male mice were distributed in 4 groups according to treatment (0.1nmol of NPS or vehicle intracerebroventricular injection) and to 20h-SR. Immediately after behavioural testing, regional c-fos immunohistochemistry was performed and used as a neural activation marker for spatial short term memory (prefrontal cortex, dorsal hippocampus) and emotional reactivity (basolateral amygdala and ventral hippocampus). Anxiety-like behaviour was assessed using elevated-plus maze task. Results showed that SR impaired short term memory performance and decreased neuronal activation in cingular cortex.NPS injection overcame SR-induced STM deficits and increased neuronal activation in infralimbic cortex. SR spared anxiety-like behavior in the elevated-plus maze. Neural activation in basolateral nucleus of amygdala and ventral hippocampus were not changed after SR.In conclusion, the present study shows that NPS overcomes SR-induced STM deficits by increasing prefrontal cortex activation independently of anxiety-like behaviour.

The present study was aimed at determining the relative contribution of the dorsal (DH) and ventral (VH) hippocampus in stress-induced memory retrieval impairments. Thus, we studied the temporal involvement of corticosterone and its receptors, i.e. mineralocorticoid (MR) and glucocorticoid (GR) in the DH and VH, in relation with the time-course evolution of stress-induced memory retrieval impairments. In a first experiment, double microdialysis allowed showing on the same animal that an acute stress (electric footshocks) induced an earlier corticosterone rise in the DH (15-60 min post-stress) and then in the VH (90-105 min post-stress). The return to baseline was faster in the DH (105 min) than in the VH (120 min). Memory deficits assessed by delayed alternation occurred at 15-, 60-, and 105-min delays after stress and were closely related to the kinetic of corticosterone rises within the DH and VH. In a second experiment, the GR antagonist RU-38486 and the MR antagonist RU-28318 were administered in the DH or VH 15 min before stress. RU-38486 restored memory at 60 but not at 105 min post-stress delays in the DH, whereas the opposite pattern was observed in the VH. By contrast, RU-28318 had no effect on memory impairments at both the 60- and 105-min post-stress delays, showing that MR receptors are not involved at these delays. However, RU-28318 administered in the DH restored memory when administered at a shorter post-stress delay (15 min). Overall, our data are first to evidence that stress induces a functional switch from the DH to VH via different corticosterone time-course evolutions in these areas and the sequential GR receptors involvement in the DH and then in the VH, as regards the persistence of stress-induced memory retrieval deficits over time.

This study was aimed at determining the type of the glucocorticoid membrane receptors (mineralocorticoid receptors (MRs) or glucocorticoid receptors (GRs)) in the dorsal hippocampus (dHPC) involved in the rapid effects of corticosterone or stress on memory retrieval. For that purpose, we synthesized corticosterone–3-O-carboxymethyloxime–bovine serum albumin conjugate (Cort–3CMO–BSA) conjugate (a high MW complex that cannot cross the cell membrane) totally devoid of free corticosterone, stable in physiological conditions. In a first experiment, we evidenced that an acute stress (electric footshocks) induced both a dHPC corticosterone rise measured by microdialysis and memory retrieval impairment on delayed alternation task. Both the endocrinal and cognitive effects of stress were blocked by metyrapone (a corticosterone synthesis inhibitor). In a second experiment, we showed that bilateral injections of either corticosterone or Cort–3CMO–BSA in dHPC 15 min before memory testing produced impairments similar to those resulting from acute stress. Furthermore, we showed that anisomycin (a protein synthesis inhibitor) failed to block the deleterious effect of Cort–3CMO–BSA on memory. In a third experiment, we evidenced that intra-hippocampal injection of RU-28318 (MR antagonist) but not of RU-38486 (GR antagonist) totally blocked the Cort–3CMO–BSA-induced memory retrieval deficit. In a fourth experiment, we demonstrated that RU-28318 administered 15 min before stress blocked the stress-induced memory impairments when behavioral testing occurred 15 min but not 60 min after stress. Overall, this study provides strong in vivo evidence that the dHPC membrane GRs, mediating the rapid and non-genomic effects of acute stress on memory retrieval, are of MR but not GR type.

This study examines the effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on serial contextual memory retrieval in non-stress and stress conditions. Independent groups of mice learned two successive contextual serial discriminations (D1 and D2) in a four-hole board. The discriminations differed each by the color and texture of the floor. Twenty-four hours later, memory testing occurred in independent groups of mice on one of the two floors of the initial acquisition session. Half of the subjects received three electric footschocks (0.9 mA, 2 s) 5 min prior to testing. Results showed that (i) stress induced a plasma corticosterone rise of same magnitude in sham-operated and MD-lesioned mice; (ii) non-stressed sham-operated mice accurately remembered D1 but not D2, whereas stressed sham-operated animals remembered D2 but not D1; (iii) non-stressed MD-lesioned mice exhibited a memory retrieval pattern similar to that observed in non-stressed sham-operated mice; (iv) however, the stress-induced inversion of the memory retrieval pattern was not observed in MD animals. The effects of MD lesions on memory retrieval in this task are similar to those observed in earlier studies in prefrontal cortex or amygdala-lesioned mice [Chauveau F, Pierard C, Coutan M, Drouet I, Liscia P, Beracochea D. Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory pattern in mice. Neurobiol Learn Mem 2008;90:395–403]; they are however in sharp contrast with mice exhibiting hippocampal lesions [Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress condition. Neurobiol Learn Mem; in press; Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus; in press]. Overall, the present findings highlight the involvement of the MD in an AMG/PFC system mediating the rapid effects of stress on serial memory retrieval.

Previous data from our team have shown that pre-test stress in mice reversed the pattern of memory retrieval in a contextual serial spatial task (CSD; Celerier, A., Pierard, C., Rachbauer, D., Sarrieau, A., & Beracochea, D. (2004). Contextual and serial discriminations: A new learning paradigm to assess simultaneously the effects of acute stress on retrieval of flexible or stable information in mice. Learning and Memory, 11 , 196–204). The present study is aimed at determining brain areas which might be critically involved in mediating the stress effect on memory retrieval in the CSD task. For that purpose, we studied hereby the effects of ibotenic acid lesions of either the prefrontal cortex (PFC) or the basolateral amygdala (BLA) in Stressed or Non-Stressed Balb/c mice on memory retrieval in the CSD task. In that task, mice learned two successive spatial discriminations (D1 and D2) within two different internal contexts in a four-hole board. The stressor (electric footshocks) was delivered 5 min before test, occurring 24 h after acquisition. During test, mice were relocated either on the floor of the first or of the second discrimination. Results showed that (i) spatial memory was substantial and remained unaffected both by lesions and stress; (ii) Non-Stressed controls as well as Non-Stressed or Stressed PFC and BLA-lesioned mice remembered accurately D1 but not D2; and (iii) in contrast, Stressed controls accurately remembered D2 but not D1. In parallel to behavioral experiments, we also showed that PFC and BLA lesions did not affect the stress-induced increase of plasma corticosterone levels. All together, PFC and BLA integrity are not necessary for retrieval processes per se; in contrast, the PFC and BLA are critically involved in the mediation of the deleterious stress effects on serial order memory retrieval.

This study investigated the dose-effect relationship of modafinil administration on contextual memory processes, in parallel with the measurements of plasma corticosterone levels in acutely stressed mice.Memory was first evaluated in normal (nonstressed) mice either in contextual (CSD) or spatial (SSD) tasks. Thus, C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board. The discriminations occurred on either distinct (CSD) or identical (SSD) floors (internal contextual cues). All mice received a vehicle intraperitoneal injection before learning and were injected 24 h later (20 min before the test session) either with vehicle or modafinil.Results showed that modafinil-treated mice behaved similarly as vehicles in the spatial SSD task, whereas in contrast, memory of the first-learned discrimination (D1) in the CSD task was enhanced by a 32- but not a 16-mg/kg modafinil dose. Hence, we studied the effect of a pretest acute stress (electric footshocks) specifically on D1 performance in modafinil-treated subjects. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels.Results showed that: (1) stress significantly improved performance in vehicles, (2) stress decreased the efficiency threshold of modafinil, as performance was enhanced at the low dose (16 mg/kg), whereas this enhancement was obtained for the high dose (32 mg/kg) under nonstress conditions, (3) the performance was impaired at the high (32 mg/kg) dose, and (4) modafinil significantly reduced the magnitude of the stress-induced corticosterone secretion, mainly at the dose of 32 mg/kg.

STUDY OBJECTIVES: Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex, but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the impact of connexins on the effects of modafinil using connexin inhibitors. METHODS: Modafinil was administered alone or combined with inhibitors of astrocyte connexin, meclofenamic acid, or flecainide, respectively, acting on Cx30 and Cx43. Sleep-wake states were monitored in wild-type and narcoleptic orexin knockout mice. A spontaneous alternation task was used to evaluate working memory in wild-type mice. The effects of the compounds on astroglial intercellular coupling were determined using dye transfer in acute cortical slices. RESULTS: Meclofenamic acid had little modulation on the effects of modafinil, but flecainide enhanced the wake-promoting and pro-cognitive effects of modafinil. Co-administration of modafinil/flecainide resulted in a marked decrease in the number and duration of direct transitions to rapid eye movement sleep, which are characteristic of narcoleptic episodes in orexin knockout mice. Furthermore, modafinil enhanced the connexin-mediated astroglial cell coupling, whereas flecainide reduced it. Finally, this modafinil-induced effect was reversed by co-administration with flecainide. CONCLUSIONS: Our study indicates that flecainide impacts the pharmacological effects of modafinil, likely through the normalization of Cx30-dependent gap junctional coupling in astroglial networks. The enhancement of the wake-promoting, behavioral, and cognitive outcomes of modafinil demonstrated here with flecainide would open new perspectives in the management of sleep disorders such as narcolepsy. COMMENTARY: A commentary on this article appears in this issue on page 1175.

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.

The effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on memory and fear reactivity in mice were studied. In the first experiment, MD subjects were submitted to a behavioral design allowing to study the relationship between memory and anxiety [Krazem A, Borde N, Beracochea D. Effects of diazepam and beta-CCM on working memory in mice: relationship with emotional reactivity. Pharmacol Biochem Behav 2001;68:235-44; Beracochea D, Krazem A, Jaffard R. Methyl beta carboline-3-carboxylate reverses the working memory deficits induced either by chronic alcohol consumption or mammillary body lesions in mice. Psychobiology 1995;23:52-8]. In a second experiment, MD-lesioned subjects were submitted to a GO/NOGO temporal alternation task involving two intertrial intervals (ITIs: 0 and 30 s). Lesioned subjects exhibited large bilateral mediodorsal thalamic lesions with small damage into the centromedial thalamic nucleus. In the first experiment, MD-lesioned animals performed normally a sequential alternation task involving fixed ITIs over seven successive trials (5 or 30 s); in contrast, MD-lesioned subjects exhibited deficits in the sequential task involving the same but mixed ITIs (30-5 s versus 5-30 s) the deficit being observed for the last trials of the series, regardless the ITIs used. MD lesions increased fear reactivity in an elevated-plus maze, and scores of anxiety were negatively correlated with performance in the mixed alternation schedule. The second experiment involving non spatial information extended results of the first experiment in showing that the deficit of MD-lesioned animals was not dependent on the ITIs separating trials. Overall, our data show that MD-lesioned subjects exhibit a cognitive impairment characterized by a difficulty to maintain an alternation rule in situations involving procedural variance, and this deficit could stem primarily from an increase of fear reactivity.

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 pre-conditioning 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.

The aim of the present work was to investigate in mice the effects of a total 10-hr sleep deprivation on contextual (episodic-like) and spatial (reference) memory tasks. For that purpose, mice learned two consecutive discriminations (D1 and D2) in a 4-hole board involving either identical (Serial Spatial Discrimination, SSD) or distinct (Contextual Serial Discrimination, CSD) internal contextual cues. In a second step, we intended to assess the corrective effect of modafinil on memory impairments generated by sleep deprivation. Sleep deprivation was triggered through an alternative platform apparatus (water box), previously validated using EEG recording and spectral analysis. We showed that a 10-hr total sleep deprivation impaired the CSD task but not the SSD one. Moreover, the impairment of contextual memory in sleep-deprived animals was dose-dependently corrected by modafinil. Indeed, modafinil administered after the sleep deprivation period and 30 min before the test session restored a memory retrieval pattern identical to non sleep-deprived animals at the doses of 32 and 64 mg/kg, however not at 16 mg/kg. Results hereby evidence that the vigilance-enhancing drug modafinil is able to restore the contextual memory performance at a low dose as compared to other memory tasks, possibly by an enhancement of hippocampal activity known to be both involved in the processing of contextual information and impaired following our sleep deprivation procedure.

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.

We previously showed that 24h after learning, mice significantly remembered the first (D1) but not the second (D2) discrimination in a serial spatial task and that an acute stress delivered 5min before the test phase reversed this memory retrieval pattern. A first experiment evaluated the effects of dorsal hippocampus (HPC) or prefrontal cortex (PFC) lesions, these two brain areas being well-known for their involvement in serial and spatial memory processes. For this purpose, six independent groups of mice were used: non-lesioned (controls), PFC or HPC-lesioned animals, submitted or not to an acute stress (electric footshocks; 0.9mA). Results show that (i) non-stressed controls as well as PFC-lesioned mice (stressed or not) remembered D1 but not D2; (ii) stressed controls and HPC-lesioned mice (stressed or not) remembered D2 but not D1; (iii) stress significantly increased plasma corticosterone in controls and PFC-lesioned mice, but not in HPC-lesioned mice which already showed a significant plasma corticosterone increase in non-stressed condition. Since data from this first experiment showed that stress inhibited the hippocampal-dependent D1 memory retrieval, a second experiment evaluated the behavioral effect of intrahippocampal corticosterone injection in non-stressed mice. Results show that intrahippocampal corticosterone injection induced a reversal of serial memory retrieval pattern similar to that induced by acute stress. Overall, our study shows that (i) in non-stress condition, the emergence of D1 is HPC-dependent; (ii) in stress condition, the emergence of D2 requires the PFC integrity; moreover, intrahippocampal corticosterone injection mimicked the effects of stress in the CSD task.

This study investigated the dose–effect of amphetamine on contextual serial (contextual serial discrimination (CSD)) and serial (serial discrimination (SD)) memory in acutely stressed versus nonstressed C57 Bl/6 Jico mice. Memory was first evaluated in nonstress condition. Mice learned two consecutive discriminations (D1 and D2) in a four-hole board involving either distinct (CSD) or identical (SD) internal contextual cues. All mice received i.p. injections of vehicle before acquisition and vehicle or amphetamine 20 min before the memory retrieval phase occurring 24 h after acquisition. Results showed that: (1) vehicle group expressed in both tasks a similar memory retrieval pattern, D2 being better retrieved than D1; (2) 2 mg/kg amphetamine significantly enhanced D1 but not D2 performance in both tasks, whereas 4 mg/kg amphetamine enhanced D2 but not D1 retrieval. Thus, amphetamine more specifically modulates serial order memory retrieval in a context-independent manner. In a further step, we studied the effect of an acute stress (electric foot shocks 5 min before retrieval) specifically on D1 performance of the CSD task in 2 mg/kg amphetamine-treated mice. Immediately after testing, blood was sampled to measure plasma corticosterone levels. Results showed that acute stress significantly improved D1 performance in vehicles but blocked the memory-enhancing effect of 2 mg/kg amphetamine, as compared to the nonstress condition. However, statistical analysis failed to evidence a significant interaction between treatments and conditions (stress vs nonstress) on corticosterone levels, contrary to another vigilance-enhancing drug, modafinil (Beracochea, Psychopharmacology 196:1–13, 2008).

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 sleep deprivation 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-h 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-h 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.

Latency for the first SRS 17.2 ±2.2 13.5 ±1.9 36.1 ±9. 25.2* ±11.5 Total seizure frequency IIIrd month Lph 22.3 ±11 52o ±17.5 18.4 ±9 12* ±5.2 Dph 5 ±3 10.5 ±7 10 ±5 3.1 ±2 Total seizure frequency IVth month Lph 19 ±5.6 59.8o ±19 13.3 ±5 9.2* ±3.8 Dph 8.6 ±3.8 17.2 ±7.7 4.6 ±1.7 2.2* ±0.5 Total seizure frequency Vth month Lph 27.7 ±12.6 80.9o ±24 44.3 ±17.8 8.4* ±3.3 Dph 13 ±5.6 35.8o ±11.5 20 ±8.9 7.1* ±1.7 OF distance in central area in OF test Lph 115.8 ±17.4 687.6 ±124.2o 152.2 ±28.7 678 ±116.5 465.3* ±79.8 653.6 ±202 375.4 ±91.8 513.1* ±136.5

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