Long-term effects of cytokine treatment on cognitive behavioral recovery and neuronal regeneration in soman-poisoned mice.

Increasing numbers of reports have substantiated to date, a beneficial influence of cytokine treatment on neurogenesis processes in damaged rodent brains. Most of these investigations further revealed that cytokine treatment induces either partial or full recovery of cognitive behavior impaired by cerebral lesions. Hence, we investigated the effects of a cytokine treatment on neuronal regeneration and cognitive behavior in mice subjected to nerve agent exposure. Subcutaneous injection of a mixture of 40 µg/kg fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) was administered daily over 8 days to soman-poisoned mice (1.2 LD50 soman). Memory performances (T-maze and Morris water maze) and emotional behavior (elevated plus maze; auditory and contextual response in a fear conditioning task) were assessed on post-soman days 30 and 90. Brains were collected on post-soman days 9, 30 and 90 so as to perform NeuN-immunohistochemistry in the hippocampus and amygdala (neuronal regeneration quantification). Following soman-induced brain lesions, a spontaneous neuronal regeneration occurred in both the hippocampus and amygdala. Cytokine treatment enhanced neuronal regeneration in the hippocampus however not in the amygdala. Soman poisoning fostered altogether memory impairments as well as anxiety or fear-like behavioral disturbances in mice. A spontaneous recovery of standard emotional behavior occurred overtime. Such a recovery displayed significantly enhanced speed under cytokine treatment. Unfortunately, no memory performance recovery was evidenced in soman-intoxicated mice whether treated or not with cytokines.

Differential effects of total sleep deprivation on contextual and spatial memory: modulatory effects of modafinil.

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.

The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress conditions.

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.

Combined effects of acute stress and amphetamine on serial memory retrieval pattern in mice.

INTRODUCTION: 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. MATERIALS AND METHODS: 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: 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 (Béracochéa, Psychopharmacology 196:1-13, 2008).

Long-term consequences of soman poisoning in mice: part 2. Emotional behavior.

The organophosphorus compound soman produces long-lasting epileptic seizure activity which is associated to brain damage, more particularly in the hippocampus and the amygdala. The companion paper (see part 1 in the same journal issue) describes the neuropathology in the amygdala of soman-poisoned mice. The present paper examines the long-term effects of soman poisoning on emotional reactivity in mice, 30 or 90 days after intoxication using behavioral tasks involving amygdala function. The emotional behavior was estimated in animal tests of unconditioned fear (light/dark boxes, elevated plus-maze) and conditioned fear (auditory and contextual response). In the light/dark boxes and elevated plus-maze, mice intoxicated with soman (110 microg/kg, 1.2 LD(50)) showed an anxiety-like behavior profile at post-poisoning days 30 and 90. In conditioned fear, results showed that both auditory and contextual conditioned responses are increased on post-soman day 30 but no longer on post-soman day 90, evidencing behavioral recovery overtime. This latter behavioral result is in accordance with the delayed neuronal regeneration patterns described in the companion paper (part 1).

Stress modulation of the memory retrograde-enhancing effects of the awakening drug modafinil in mice.

PURPOSE: 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. MATERIALS AND METHODS: 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: 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. CONCLUSIONS: 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.

Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice.

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.

Long-term behavioral consequences of soman poisoning in mice.

We investigated the long-term (up to 90 days) consequences of soman intoxication in mice on weight, motor performances (grip strength, rotarod) and mnemonic cognitive processes (T-maze, Morris water maze test). First, a relative weight loss of 20%, measured 3 days after intoxication, was evidenced as a threshold beyond which neuropathological damage was observed in the hippocampus. Animals were then distributed into either low weight loss (LWL) or high weight loss (HWL) groups according to the relative 20% weight loss threshold. Compared to controls, both groups of poisoned mice quickly exhibited a decrease in their motor performance subsequent to an acute soman toxicity phase. Then, total motor recovery occurred for the LWL group. Comparatively, HWL mice showed only transient recovery prior to a second decrease phase due to soman-induced delayed toxicity. One month after intoxication, mnemonic cognitive performances of the LWL group were similar to controls while the HWL group did not exhibit any learning skill. Three months after poisoning, compared to controls, the LWL group showed similar mnemonic performances in the maze test but a mild deficit in the Morris water maze task. At the same time, learning skills slightly recovered in the HWL group. Mnemonic cognitive data are discussed in relation to the neuropathology, neurogenesis and sprouting occurring in the hippocampus of soman-intoxicated animals.

Modafinil-induced modulation of working memory and plasma corticosterone in chronically-stressed mice.

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.

Declarative memory impairments following a military combat course: parallel neuropsychological and biochemical investigations.

The aim of this study was to investigate the impact on several forms of memory and metabolism of a 5-day combat course including heavy and continuous physical activities and sleep deprivation. Mnemonic performance and biochemical parameters of 21 male soldiers were examined before and at the end of the course. Our results showed that short-term memory (memory span, visual memory, audiovisual association) and long-term memory were significantly impaired, whereas short-term spatial memory and planning tasks were spared. Parallel biochemical analysis showed an adaptation of energy metabolism. The observed decrease in glycaemia may be partly responsible for the long-term memory impairment, whereas the decreases in plasma cholinesterases and choline may be involved in the short-term memory deterioration. However, there are also many other reasons for the observed memory changes, one of them being chronic sleep deprivation.