Karina A. Zanin

Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: mood-congruent memory in male mice?

BACKGROUND Although mood-congruent memory (MCM), or the tendency to recall information consistent with ones mood, is a robust phenomenon in human depression, to our knowledge, it has never been demonstrated in animals. METHODS Mice were subjected to social isolation (SI) or crowding for 12 hours and had their depressive-like behaviour (evaluated by the forced swim, tail suspension, sucrose preference and splash tests) or their serum corticosterone concentrations evaluated. In addition, we determined the temporal forgetting curve of the plus-maze discriminative avoidance task (PM-DAT) and examined the effects of SI or crowding on memory retrieval in the PM-DAT. Finally, we verified the effects of metyrapone pretreatment on reinstatement of memory retrieval or on the increase of corticosterone levels induced by SI. RESULTS Twelve hours of SI produced depressive-like behaviour, enhanced corticosterone concentration and reinstated retrieval of a forgotten discriminative aversive (i.e., negatively valenced) task. Depressive-like behaviour was critical for this facilitative effect of SI because 12 hours of crowding neither induced depressive-like behaviour nor enhanced retrieval, although it increased corticosterone levels at the same magnitude as SI. However, corticosterone increase was a necessary condition for MCM in mice, in that the corticosterone synthesis inhibitor metyrapone abolished SI-induced retrieval reinstatement. LIMITATIONS Our study did not investigate the effects of the social manipulations proposed here in a positively valenced task. CONCLUSION To our knowledge, the present paper provides the first evidence of MCM in animal models.

Sleep deprivation impairs emotional memory retrieval in mice: Influence of sex

The deleterious effects of paradoxical sleep deprivation on memory processes are well documented. However, non-selective sleep deprivation occurs more commonly in modern society and thus represents a better translational model. We have recently reported that acute total sleep deprivation (TSD) for 6 h immediately before testing impaired performance of male mice in the plus-maze discriminative avoidance task (PM-DAT) and in the passive avoidance task (PAT). In order to extend these findings to females, we examined the effect of (pre-test) TSD on the retrieval of different memory tasks in both male and female mice. Animals were tested using 3 distinct memory models: 1) conditioning fear context (CFC), 2) PAT and 3) PM-DAT. In all experiments, animals were totally sleep-deprived by the gentle interference method for 6h immediately before being tested. In the CFC task and the PAT, TSD induced memory impairment regardless of sex. In PM-DAT, the memory impairing effects of TSD were greater in females. Collectively, our results confirm the impairing effect of TSD on emotional memory retrieval and demonstrate that it can be higher in female mice depending on the memory task evaluated.

Role of state-dependency in memory impairment induced by acute administration of midazolam in mice

Although the memory deficits produced by pre-training benzodiazepines administration have been extensively demonstrated both in humans and in animal studies, there is considerable controversy about the involvement of the state-dependency phenomenon on benzodiazepines-induced anterograde amnesia. The present study aimed to characterize the role of state-dependency on memory deficits induced by the benzodiazepine midazolam (MID) in mice submitted to the plus-maze discriminative avoidance task (PM-DAT). This animal model concomitantly evaluates learning and retention of discriminative avoidance task, exploratory habituation as well as anxiety-like behavior and motor activity. Mice received 2mg/kg MID before training and/or before testing in the PM-DAT. Pre-training (but not pre-test) MID administration impaired the retention of the discriminative avoidance task, which was not counteracted by a subsequent pre-test administration of this drug, thus refuting the role of state-dependency. Conversely, the pre-training administration of MID also led to an impairment of the habituation of exploration in the PM-DAT (an animal model of non-associative memory). This habituation deficit was state-dependent since it was absent in pre-training plus pre-test MID treated mice. Concomitantly, MID pre-training administration induced anxiolytic effects and diminished the aversive effectiveness of the aversive stimuli of the task, leading to an impairment of the acquisition of the discriminative avoidance task. Our findings suggest that pre-training benzodiazepine administration can impair the retention of different types of memory by producing specific deleterious effects on learning or by inducing state-dependent memory deficits.

Ethanol-Induced Memory Impairment in a Discriminative Avoidance Task is State-Dependent

BACKGROUND A considerable amount of experimental evidence has demonstrated ethanol (EtOH) induced amnestic effects following EtOH administration during pretraining in a variety of tasks both in humans and in laboratory animals. Although the phenomenon of state-dependency is known to play a critical role in memory deficits induced by both pharmacological and nonpharmacological pretraining perturbations, the involvement of this phenomenon in EtOH-induced anterograde amnesia has been overlooked. This study aimed to investigate the role of state-dependency in EtOH-induced amnestic effects and its interactions with the well-known anxiolysis and locomotor alterations. METHODS Mice were treated with 1.2 or 2.4 g/kg EtOH before training and/or before testing in the plus-maze discriminative avoidance task, an animal model that concomitantly evaluates learning, memory, anxiety-like behavior, and general activity. RESULTS Whereas both doses of EtOH induced anxiolysis, the 1.2 g/kg dose enhanced locomotion while the 2.4 g/kg dose decreased it. In addition, the administration of 1.2 g/kg of this drug during pretraining caused memory impairment, which was counteracted by the pretest administration of the same dose, revealing the participation of the state-dependency. Conversely, the administration of 2.4 g/kg EtOH led to amnestic effects irrespective of the time of the administration (pretraining and/or pretest), eliminating the influence of state-dependency. CONCLUSIONS Our data demonstrate that EtOH-induced memory deficits are critically related to state-dependency, which can also be affected by the dose range. These results indicate the possible participation of EtOH-induced modifications in anxiety and motor activity levels in relation to state-dependent memory deficits.

Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task

RationaleZolpidem (Zolp), a hypnotic drug prescribed to treat insomnia, may have negative effects on memory, but reports are inconsistent.ObjectivesWe examined the effects of acute doses of Zolp (2, 5, or 10 mg/kg, i.p.) on memory formation (learning, consolidation, and retrieval) using the plus-maze discriminative avoidance task.MethodsMice were acutely treated with Zolp 30 min before training or testing. In addition, the effects of Zolp and midazolam (Mid; a classic benzodiazepine) on consolidation at different time points were examined. The possible role of state dependency was investigated using combined pre-training and pre-test treatments.ResultsZolp produced a dose-dependent sedative effect, without modifying anxiety-like behavior. The pre-training administration of 5 or 10 mg/kg resulted in retention deficits. When administered immediately after training or before testing, memory was preserved. Zolp post-training administration (2 or 3 h) impaired subsequent memory. There was no participation of state dependency phenomenon in the amnestic effects of Zolp. Similar to Zolp, Mid impaired memory consolidation when administered 1 h after training.ConclusionsAmnestic effects occurred when Zolp was administered either before or 2–3 h after training. These memory deficits are not related to state dependency. Moreover, Zolp did not impair memory retrieval. Notably, the memory-impairing effects of Zolp are similar to those of Mid, with the exception of the time point at which the drug can modify consolidation. Finally, the memory effects were unrelated to sedation or anxiolysis.

Sleep deprivation impairs the extinction of cocaine-induced environmental conditioning in mice.

Persistence of a drug-environment conditioning induced by repeated psychostimulant treatment is thought to play a key role in the addictive cycle. In addition, sleep disorders are a common feature in patients with addictive disorders. Sleep deprivation shares similar neurobiological effects with psychostimulants. Therefore, we investigated whether sleep deprivation would impair the extinction of previously established conditioning between the drug effect and the environmental cues. Four cohorts of male adult mice underwent a behavioral sensitization procedure pairing drug (cocaine at 15 mg/kg, i.p.) or saline with environment (open-field apparatus). The extinction of conditioned locomotion was evaluated after control (home-cage maintained) or sleep deprivation (gentle handling method for 6h) conditions. Sleep deprivation both postponed the initiation and impaired the completeness of extinction of the conditioned locomotion promoted by previous drug-environment conditioning in cocaine-sensitized animals. While the cocaine control group required 5 free-drug sessions of exposure to the open-field apparatus to complete extinction of conditioned locomotion, the cocaine pre-treated group that experienced sleep deprivation before each extinction session still significantly differed from its respective control group on Day 5 of extinction. The possibility that the sleep condition can influence the extinction of a long-lasting association between drug effects and environmental cues can represent new outcomes for clinically relevant phenomena.

Sleep Deprivation Increases Mortality in Female Mice Bearing Ehrlich Ascitic Tumor

Objectives: Sleep deprivation is a growing public health hazard, yet it is still under-recognized. Sleep disorders and disruption of sleep patterns may compromise the immune function and adversely affect host resistance to infectious diseases. This is a particular risk in cancer patients, who report a high frequency of sleep disturbances. The present study investigated the effects of sleep deprivation on the development of Ehrlich ascitic tumors (EAT) in female BALB/c mice. Our study also evaluated whether EAT would induce alterations in sleep pattern. Spleen lymphocyte cell populations and mortality were also quantified. Methods: Female BALB/c mice were intraperitoneally inoculated with EAT cells. Immediately after the inoculation procedure, animals were sleep deprived for 72 h. Ten or 15 days after inoculation, the number of tumoral cells was quantified and the lymphocytic cell population in the spleen was characterized by flow cytometry. In addition, the effect of sleep deprivation on EAT-induced mortality was quantified and the influence of EAT on sleep patterns was determined. Results: Sleep deprivation did not potentiate EAT growth, but it significantly increased mortality. Additionally, both EAT and sleep deprivation decreased frequencies of splenic CD4+, CD8+ and CD19+ cells. With respect to sleep patterns, EAT significantly enhanced paradoxical sleep time. Conclusions: Although sleep deprivation did not potentiate EAT growth, it decreased the survival of female tumor-bearing mice.

Role of state-dependent learning in the cognitive effects of caffeine in mice

Caffeine is the most widely used psychoactive substance in the world and it is generally believed that it promotes beneficial effects on cognitive performance. However, there is also evidence suggesting that caffeine has inhibitory effects on learning and memory. Considering that caffeine may have anxiogenic effects, thus changing the emotional state of the subjects, state-dependent learning may play a role in caffeine-induced cognitive alterations. Mice were administered 20 mg/kg caffeine before training and/or before testing both in the plus-maze discriminative avoidance task (an animal model that concomitantly evaluates learning, memory, anxiety-like behaviour and general activity) and in the inhibitory avoidance task, a classic paradigm for evaluating memory in rodents. Pre-training caffeine administration did not modify learning, but produced an anxiogenic effect and impaired memory retention. While pre-test administration of caffeine did not modify retrieval on its own, the pre-test administration counteracted the memory deficit induced by the pre-training caffeine injection in both the plus-maze discriminative and inhibitory avoidance tasks. Our data demonstrate that caffeine-induced memory deficits are critically related to state-dependent learning, reinforcing the importance of considering the participation of state-dependency on the interpretation of the cognitive effects of caffeine. The possible participation of caffeine-induced anxiety alterations in state-dependent memory deficits is discussed.

Short-term sleep deprivation reinstates memory retrieval in mice: the role of corticosterone secretion.

While the effects of sleep deprivation (SD) on the acquisition and consolidation phases of memory have been extensively characterized, its effects on memory retrieval remain overlooked. SD alone is a stressor, and stress-activated glucocorticoids promote bimodal effects on memory. Because we have recently demonstrated that 72h SD impairs memory retrieval in the plus-maze discriminative avoidance task (PM-DAT) in mice, this study investigated whether shorter SD periods would facilitate retrieval. In Experiment I, the temporal forgetting curve of the PM-DAT was determined and an interval between training/testing in which retrieval was no longer present was used in all subsequent experiments. In Experiments II and III, retrieval performance and corticosterone concentration, respectively, were quantified in mice that were sleep deprived for 12 or 24h before testing. In Experiments IV and V, the effects of the corticosterone synthesis inhibitor metyrapone were evaluated on 12h SD-induced retrieval reinstatement and corticosterone concentration enhancement, respectively. Experiment VI determined whether pre-test acute administration of exogenous corticosterone would mimic the facilitatory effects of 12h SD on retrieval. Thirty days after training, mice presented poor performance of the task; however, SD for 12h (but not for 24) before testing reinstated memory retrieval. This facilitatory effect was accompanied by increased corticosterone concentration, abolished by metyrapone, and mimicked by pre-test acute corticosterone administration. Collectively, short-term SD can facilitate memory retrieval by enhancing corticosterone secretion. This facilitatory effect is abolished by longer periods of SD.

Effects of prenatal immune activation on amphetamine-induced addictive behaviors: Contributions from animal models

BACKGROUND Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents. OBJECTIVES Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross-sensitization with cocaine (COC) were also investigated. METHODS Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross-sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days. RESULTS Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross-sensitization with COC. CONCLUSIONS Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior.