Synergistic effects of Lacticaseibacillus rhamnosus GG, glutamine, and curcumin on chronic unpredictable mild stress-induced depression in a mouse model.

The microbiota-gut-brain axis is important in anxiety-depressive disorders. These conditions are associated with dysbiosis of the intestinal microbiota, intestinal hyperpermeability and an increase in circulating markers of inflammation and oxidative stress. They are also associated with a deregulation of the glutamine-glutamate-γ-aminobutyric acid cycle, with impairment of the excitatory/inhibitory balance in the brain. Our aim was to examine the impact of chronic treatment with the probiotic organism Lacticaseibacillus rhamnosus GG, alone or in combination with glutamine and curcumin, in a validated model of anxiety-depressive disorder in mice. Six-month-old mice (n=144) were exposed to chronic unpredictable mild stress (CUMS) stimulation for 3 weeks and emotional disturbances were assessed using two tests assessing anxiety (elevated plus maze test) and depressive-like behaviour (tail suspension test). After discontinuation of CUMS, mice were force-fed once-daily with curcumin, glutamine and probiotic alone or in combination for 21 consecutive days. Emotional reactivity was assessed in two separate behavioural tests: open field test and forced swim test. The outcomes of the interventions were compared with those induced by acute intraperitoneal administration of clomipramine, one of the major tricyclic antidepressants used in humans. Two independent sets of experiment were performed in this study, in order to evaluate the effects of two different formulations based on the utilisation of the probiotic L. rhamnosus GG in its live or inactivated form. CUMS led to an impairment of the emotional state of 6-month-old mice. However, chronic treatment with a combination of glutamine, curcumin and L. rhamnosus GG rescued the anxiety and depressive-like phenotype with an efficiency similar to clomipramine. A synergistic effect of the three compounds was observed, suggesting that simultaneous action on different targets is a relevant approach for the management of anxiety-depressive disorders.

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice.

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer's disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.

Different implications of the dorsal and ventral hippocampus on contextual memory retrieval after stress.

This study assessed the relative contributions of dorsal (dHPC) and ventral (vHPC) hippocampus regions in mediating the rapid effects of an acute stress on contextual memory retrieval. Indeed, we previously showed that an acute stress (3 electric footschocks; 0.9 mA each) delivered 15 min before the 24 h-test inversed the memory retrieval pattern in a contextual discrimination task. Specifically, mice learned in a four-hole board two successive discriminations (D1 and D2) varying by the color and texture of the floor. Twenty-four hours later, nonstressed animals remembered accurately D1 but not D2 whereas stressed mice showed an opposite memory retrieval pattern, D2 being more accurately remembered than D1. We showed here that, at the time of memory testing in that task, stressed animals exhibited no significant changes neither in pCREB activity nor in the time-course evolution of corticosterone into the vHPC; in contrast, a significant decrease in pCREB activity and a significant increase in corticosterone were observed in the dHPC as compared to nonstressed mice. Moreover, local infusion of the anesthetic lidocaine into the vHPC 15 min before the onset of the stressor did not modify the memory retrieval pattern in nonstress and stress conditions whereas lidocaine infusion into the dHPC induced in nonstressed mice an memory retrieval pattern similar to that observed in stressed animals. The overall set of data shows that memory retrieval in nonstress condition involved primarily the dHPC and that the inversion of memory retrieval pattern after stress is linked to a dHPC but not vHPC dysfunction.

Rescuing prefrontal cAMP-CREB pathway reverses working memory deficits during withdrawal from prolonged alcohol exposure.

Both human and animal studies indicate that alcohol withdrawal following chronic alcohol consumption (CAC) impairs many of the cognitive functions which rely on the prefrontal cortex (PFC). A candidate signaling cascade contributing to memory deficits during alcohol withdrawal is the protein kinase A (PKA)/cAMP-responsive element binding (CREB) cascade, although the role of PKA/CREB cascade in behavioral and molecular changes during sustained withdrawal period remains largely unknown. We demonstrated that 1 week (1W) or 6 weeks (6W) withdrawal after 6-month CAC impairs working memory (WM) in a T-maze spontaneous alternation task and reduces phosphorylated CREB (pCREB) in the PFC but not the dorsal CA1 region (dCA1) of the hippocampus compared with CAC and water conditions. In contrast, both CAC-unimpaired and withdrawn-impaired mice exhibited decreased pCREB in dCA1 as well as reduced histone H4 acetylation in PFC and dCA1, compared with water controls. Next, we showed that enhancing CREB activity through rolipram administration prior to testing improved WM performance in withdrawn mice but impaired WM function in water mice. In addition, WM improvement correlates positively with increased pCREB level selectively in the PFC of withdrawn mice. Results further indicate that direct infusion of the PKA activator (Sp-cAMPS) into the PFC significantly improves or impairs, respectively, WM performance in withdrawn and water animals. In contrast, Sp-cAMPS had no effect on WM when infused into the dCA1. Collectively, these results provide strong support that dysregulation of PKA/CREB-dependent processes in prefrontal neurons is a critical molecular signature underlying cognitive decline during alcohol withdrawal.

Ciproxifan improves working memory through increased prefrontal cortex neural activity in sleep-restricted mice.

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<0.001) and was followed by sleep rebound (58.2±5.9%, p<0.05). Sleep restriction did not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5 s) inter-trial intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles, ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of Fos labelling in prelimbic, infralimbic and cingulate 2 cortex. In conclusion, ciproxifan at 3 mg/kg enhanced WM in sleep restricted mice through specific modulation of prefrontal cortex areas.

Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain.

Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids.

Stress-induced memory retrieval impairments: different time-course involvement of corticosterone and glucocorticoid receptors in dorsal and ventral hippocampus.

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.

Effects of positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in a benzodiazepine-induced deficit of spatial discrimination in mice.

Imbalance between GABAergic and glutamatergic neurotransmission has been recently hypothesized to trigger memory decline related either to ageing or to Alzheimer's disease (AD). Thereby, benzodiazepine-induced anterograde amnesia has been construed as a model of hippocampal-related cognitive dysfunctions. Since spatial memory is altered both by ageing and by benzodiazepines such as alprazolam, we investigated the pharmacological sensitivity of alprazolam-induced deficit in a delayed spatial discrimination (SD) task, notably with positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. We showed that alprazolam (0.1 mg/kg intraperitoneally) induced memory impairments as compared with vehicle-treated mice. The oral administration of modulators of AMPA receptors (IDRA-21: 10 mg/kg; S18986: 3 and 10 mg/kg) reversed the alprazolam-induced deficits. This study is first to show evidence that reference treatments of AD, such as memantine (a NMDA receptor antagonist) at 3 mg/kg per os (po) and donepezil (an acetylcholinesterase inhibitor) at 1 mg/kg po, also reversed the alprazolam-induced amnesia. Given such results, the SD task emerges as a valuable novel task to screen pro-cognitive compounds. Thus, we highlight the efficacy of modulators of AMPA-type glutamate receptors to counteract alprazolam-induced spatial deficits. These results could be viewed alongside the imbalance between excitation and inhibition observed during normal and pathological ageing.

Pharmacological modulation of contextual "episodic-like" memory in aged mice.

Episodic memory deficits in elderly are due to the progressive weaknesses to use the contextual and temporal cues of the to be remembered information. Since the inability to remember the specific context of events is an important feature of episodic memory deficits in the elderly, we first focused on describing two mice models of contextual "episodic-like" memory. In a second part, we described the effects of aging on memory in the contextual and serial discrimination (CSD) task. We showed more specifically that the CSD task allowed detection of early memory impairments in middle-aged (14-15 months) animals as compared to young (4-5 months) or aged (18-19 months) ones. Interestingly, the very same memory impairments were observed following dorsal hippocampal lesions in young adult mice, which suggest that the CSD task allowed detection of early signs of age-related hippocampal dysfunction. In a third part, we showed that pharmacological reference compounds such as donepezil and memantine (mainly used in the treatment of mild to severe forms of Alzheimer's diseases) reversed the age-induced memory impairments as well as emerging pharmacological compounds acting on different neurotransmitter targets (nicotinic and AMPA receptors). Thus, the CSD task appears to be a reliable behavioural tool for detecting the early emergence of age-related memory dysfunction and for identifying new pharmacological targets and therapeutic strategies in the treatment of age-related amnesia.

Increased stress-induced intra-hippocampus corticosterone rise associated with memory impairments in middle-aged mice.

The present study investigates the relationships between hippocampal corticosterone concentrations and memory retrieval performance in stress and non-stress conditions, in both young (6 month-old) and middle-aged (16 month-old) mice. For this purpose, the time-course evolution of stress-induced corticosterone rise in the dorsal hippocampus (dHPC) was investigated in both young and middle-aged mice. In parallel, the evolution of memory retrieval patterns was assessed using a contextual serial discrimination task (CSD). Finally, metyrapone (corticosterone synthesis inhibitor) was administered in order to evaluate the stress-induced impact of corticosterone rise on contextual memory retrieval in middle-aged animals. Results showed that: (i) non-stressed middle-aged mice exhibited a memory retrieval pattern opposite to that of non-stressed young animals, but similar to that of stressed young mice; (ii) the impact of stress on memory performance was transient (90 min) in young, as compared to middle-aged mice (120 min); (iii) dHPC basal (non-stress) corticosterone level was significantly increased by ageing; (iv) acute stress induced a rapid (15 min) and transient (90 min) dHPC corticosterone rise in young mice, while exhibiting greater magnitude and duration (120 min) in middle-aged animals; and (v) both the stress-induced endocrinal and memory effects were blocked by metyrapone in young and middle-aged mice. Finally, to our knowledge, the present work is the first study to directly measure the corticosterone rise in the hippocampus following exposure to stress and to directly correlate the corticosterone changes in the hippocampus with memory performance in both young and middle-aged mice.

Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern.

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.

Intrahippocampal cholinesterase inhibition induces epileptogenesis in mice without evidence of neurodegenerative events.

The mechanisms of epileptogenesis remain largely unknown and are probably diverse. The aim of this study was to investigate the role of focal cholinergic imbalance in epileptogenesis. To address this question, we monitored electroencephalogram (EEG) activity up to 12 weeks after the injection of a potent cholinesterase (ChE) inhibitor (soman) at different doses (0.53, 0.75, 1, 2, 2.8, 4 and 11 nmol) into the right dorsal hippocampus of C57BL/6 mice. Different parameters were used to choose the dose for a focal model of epileptogenesis (mainly electrographic patterns and peripheral ChE inhibition). The pattern of neuronal activation was studied by Fos immunohistochemistry (IHC). Brain damage was evaluated by hemalun-phloxin, neuronal nuclei antigen IHC and silver staining. Glial fibrillary acidic protein IHC was used to evaluate astroglial reaction. Finally, long-term behavioral consequences were characterized. At the highest dose (11 nmol), soman quickly evoked severe signs, including initial seizures and promoted epileptogenesis in the absence of tissue damage. With lower doses, late-onset seizures were evidenced, after 1-4 weeks depending on the dose, despite the absence of initial overt seizures and of brain damage. Only a weak astroglial reaction was observed. Following injection of 1 nmol, Fos changes were first evidenced in the ipsilateral hippocampus and then spread to extrahippocampal areas. A selective deficit in contextual fear conditioning was also evidenced two months after injection. Our data show that focal hypercholinergy may be a sufficient initial event to promote epilepsy and that major brain tissue changes (cellular damage, edema, neuroinflammation) are not necessary conditions.

Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory retrieval pattern in mice.

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.

Improvement of episodic contextual memory by S 18986 in middle-aged mice: comparison with donepezil.

INTRODUCTION: This study compared the effects of S 18986, a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, to those of donepezil a cholinesterase inhibitor on memory impairments induced by ageing in a contextual serial discrimination (CSD) task in middle-aged mice. MATERIALS AND METHODS: The CSD task involved the learning of two consecutive discriminations in a four-hole board, each performed on two different floors. This model has been developed to study simultaneously different forms of memory in mice (i.e., episodic-like vs semantic-like forms of memory). We showed that placebo-middle-aged mice (14-15 months old) and placebo-aged subjects (19-20 months old) exhibited a severe memory deficit for the first but not the second discrimination, which was due to an increase in interference, as compared with placebo-treated young mice (5 months old). Middle-aged mice were given (9 days) per os administration of either donepezil, S 18986, or placebo. RESULTS AND DISCUSSION: Both 0.3 mg/kg donepezil and 0.1 mg/kg S 18986 reversed the deficit of middle-aged mice through a significant increase in contextually correct responses and in parallel a tendency to reduce interfering responses. CONCLUSION: Overall, S 18986 emerges as having a beneficial impact on contextual memory processes in middle-aged mice.

BetaCCM enhances retrieval of serial contextual but not of serial spatial memory in mice.

The effects of inverse agonists of the gamma-aminobutyric acid (GABA)/benzodiazepine receptors such as beta-carboline-3-carboxylate (betaCCM) on retrieval processes have not been studied extensively. This study investigates the effects in mice of an acute betaCCM injection on retrieval of previously acquired serial discriminations, involving distinct contextual cues (Contextual Serial Discrimination, CSD) or identical cues (Serial Spatial Discrimination, SSD) in a four-hole board. Animals submitted to CSD were also evaluated for emotional reactivity in an elevated-plus maze. In both the CSD and the SSD tasks, mice were injected with saline before the learning session began. Twenty-four hours later, mice were replaced on the hole-board following a single dose of saline or betaCCM (0.5 mg/kg or 1.5 mg/kg) injected 20 min before testing. The highest dose of betaCCM improved performance of the first discrimination in the contextual task but not in the spatial task. Moreover, the higher dose of betaCCM produced anxiety-like reactivity in an elevated-plus maze, and scores of 'anxiety' were positively correlated with memory scores. Overall, the data show that the betaCCM enhancement of memory processes depends on: (1) the cues associated with the to-be-remembered information; and (2) the emotional effects of the drug.

A retinoic acid receptor antagonist suppresses brain retinoic acid receptor overexpression and reverses a working memory deficit induced by chronic ethanol consumption in mice.

BACKGROUND: Chronic ethanol consumption induces disorders in the biosynthesis of retinoic acid, an active derivative of vitamin A. Recent evidence suggests that an alteration in the retinoic acid signaling pathway leads to impairments in learning and memory in adult mice. We have previously shown that chronic ethanol consumption in mice produces an increased expression of the brain retinoic acid receptor beta (RARbeta) mRNA. These results prompted us to examine whether suppressing the overexpression of retinoid receptors in alcohol-treated mice by RAR antagonist administration would reverse their cognitive impairment. METHODS: After 10 months of ethanol consumption (12% v/v in drinking water), C57BL/6 mice were submitted to a working memory task in a T-maze. Then, mice of the control and the ethanol-treated groups received an RARbeta antagonist (CD2665 0.6 mg/kg) for 22 days. The behavioral effect of CD2665 administration was evaluated on a spontaneous alternation task and the neurochemical effect was measured by quantifying the mRNA expression of RARalpha, RARbeta, retinoid X receptor (RXRbeta/gamma) and tissue transglutaminase (tTG; a retinoic acid-target gene). RESULTS: Mice submitted to ethanol treatment exhibited a progressive decrease in spontaneous alternation rates over successive trials. Moreover, these mice displayed an increased expression of brain RARbeta and RXRbeta/gamma mRNA, together with an increased level of tTG mRNA and enzymatic activity. The administration of CD2665 to alcohol-treated mice totally reversed the working memory deficit and suppressed the overexpression of brain RARbeta, RXRbeta/gamma and tTG mRNA, whereas the same treatment in control mice decreased only the RARbeta mRNA level without affecting memory performance. CONCLUSION: These data point to the potential role of the retinoid signaling pathway in memory processes and suggest that the overexpression of brain RARbeta and RXRbeta/gamma could be responsible, at least in part, for some memory impairments observed during chronic ethanol consumption.

Effects of diazepam and beta-CCM on working memory in mice: relationships with emotional reactivity.

This study was aimed at determining the effects of systemic administration of diazepam and methyl beta-carboline-3-carboxylate (beta-CCM) both on spatial working memory and on emotional reactivity in mice. Results showed that diazepam and beta-CCM induced opposite effects in both memory and emotional reactivity tests. Indeed, as a function of dose, diazepam reduced anxiogenic-like reactions but increased vulnerability to interference in the memory task at a 30-s but not at a 5-s delay interval. As a function of dose, beta-CCM reduced vulnerability to interference and increased emotional reactivity, these effects being antagonised by concurrent administration of flumazenil (RO 15-1788). Thus, our study showed the bidirectional effects of these two drugs on a spatial working memory task involving a spontaneous processing of information and suggested a direct link between the emotional effects of the drugs and memory performance.

First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice.

This study investigated the effects of pretest injection of modafinil on delayed spontaneous alternation rates (SA) used to evaluate working memory in C57 Bl/6 mice. In a first experiment, systemic modafinil at 64 mg/kg, but not at 8 mg/kg or 32 mg/kg doses produced a significant increase of alternation scores (intertrial interval (ITI) 60s) when compared with controls. In a second experiment, modafinil (64 mg/kg) enhanced the alternation rates mainly at long (60 s and 180 s) but not at short (5 s) ITIs. Exploratory latencies and activity in a four hole-board apparatus were not modified by modafinil administration. These experiments are the first to demonstrate a delay-dependent working memory-enhancing effect of modafinil.

[Animal models of amnesia of alcoholic origin: an amnesia without memory impairment]. / Modèle animal de l'amnésie d'origine alcoolique: une amnésie sans atteinte de la mémoire.

Our studies show that chronic alcohol consumption (CAC) in Balb/c mice induces (1) a deficit of spontaneous but not effortful retrieval processes, and (2) a concomitant reduction of anxiety, suggesting a potential interaction between emotional and memory disorders. We have shown that the benzodiazepine agonist, diazepam, induces memory deficits similar to those produced by CAC, whereas administering beta CCM (an inverse agonist of the benzodiazepine receptor) alleviated the memory deficits of alcohol-treated subjects. Parallel neuroanatomical studies have shown that CAC produced cell damage in the mamillary bodies, whereas no major changes were observed in the hippocampus or the frontal cortex, which is involved in long-term consolidation processes. Overall data show that CAC induced amnesia is not due to a dysfunction of the neural networks underlying memory storage processes, but rather results from a difficulty in activating the neural substrates engaged in retrieval processes which depend on emotional, motivational or environmental factors.

Deficits of spatial and non-spatial memory and of auditory fear conditioning following anterior thalamic lesions in mice: comparison with chronic alcohol consumption.

This study was aimed at determining (i) whether or not bilateral subtotal lesions of the anterior thalamic nuclei (ATH) in rodents produced memory deficits for spatial and/or non-spatial information and of auditory fear conditioning, and (ii) if these eventual deficits resemble those produced by chronic alcohol consumption (CAC). Working memory was assessed using both spatial (spontaneous alternation) and non-spatial (temporal alternation) delayed response tasks. Results showed that ATH lesions induced delay-dependent memory impairments in both spatial and non-spatial alternation tasks, as well as a decreased level of auditory and background contextual fear conditioning compared with respective controls. CAC did not induce accelerated rate of forgetting in the spatial and non-spatial tasks, but increased the vulnerability to interference in the spatial task. CAC impaired only background contextual fear conditioning. We conclude that ATH nuclei are involved in the maintenance of information over time, regardless of the nature (spatial vs. non-spatial) of the information, and play a role in associative processes for both unimodal (the tone) and polymodal (contextual) information. In contrast, ATH dysfunction does not account for the memory disorders induced by the CAC treatment. Our results contribute to showing that the functional overlap between the structures comprising the hippocampo-mamillo-thalamic pathway is only partial.