Camilla L. Patti

Paradoxical sleep deprivation impairs acquisition, consolidation, and retrieval of a discriminative avoidance task in rats

The aim of the present study was to investigate the effects of paradoxical sleep deprivation (PSD) for 96 h on the learning/memory processes in rats submitted to the plus-maze discriminative avoidance task (PM-DAT), which simultaneously evaluates learning, memory, anxiety and motor function. Four experiments were performed in which rats were submitted to: (1) post-training and pre-test PSD; (2) post-training or pre-test PSD; (3) pre-training PSD or pre-training paradoxical sleep (PS) rebound (24 h) and (4) pre-test PSD rebound. Concerning Experiment I, post-training and pre-test PSD induced memory deficits, an anxiolytic-like behavior and an increase in locomotor activity. In Experiment II, both post-training PS-deprived and pre-test PS-deprived groups showed memory deficits per se. However, only the pre-test PS-deprived animals presented anxiolytic-like behavior and increased locomotor activity. In Experiment III, pre-training PS-deprived rats showed learning and memory deficits, anxiolytic-like behavior and increased locomotor activity. A 24h-sleep recovery period after the PSD abolished the learning and memory deficits but not anxiety and locomotor alterations. Finally, sleep rebound did not modify acquisition (Experiment III) and retrieval (Experiment IV). This study strengthened the critical role of paradoxical sleep (but not sleep rebound) in all the phases of learning and memory formation. In addition, it suggests that PSD effects on acquisition and consolidation do not seem to be related to other behavioral alterations induced by this procedure.

Behavioral characterization of morphine effects on motor activity in mice

A biphasic effect of morphine on locomotion has been extensively described. Nevertheless, the effects of this opioid on other behavioral parameters have been overlooked. The aim of the present study was to verify the effects of different doses of morphine on motor behaviors observed in an open-field. Adult female mice were injected with saline or morphine (10, 15 and 20 mg/kg, i.p.) and observed in an open-field for quantification of locomotor and rearing frequencies as well as duration of immobility and grooming. The lowest dose of morphine decreased locomotion (and increased immobility duration) while the highest dose increased it. All doses tested decreased rearing and grooming. Thus, the effects of morphine on locomotion do not parallel to its effects on rearing and grooming. Our results indicate that locomotion not always reflects the effect of drugs on motor activity, which can be better investigated when other behavioral parameters are concomitantly taken into account.

Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of Alzheimer's disease

Alzheimer’s disease (AD) is clinically characterized by progressive memory loss, behavioral and learning dysfunction and cognitive deficits, such as alterations in social interactions. The major pathological features of AD are the formation of senile plaques and neurofibrillary tangles together with neuronal and vascular damage. The double transgenic mouse model of AD (2xTg-AD) with the APPswe/PS1dE9 mutations shows characteristics that are similar to those observed in AD patients, including social memory impairment, senile plaque formation and vascular deficits. Mesenchymal stem cells (MSCs), when transplanted into the brain, produce positive effects by reducing amyloid-beta (Aβ) deposition in transgenic amyloid precursor protein (APP)/presenilins1 (PS1) mice. Vascular endothelial growth factor (VEGF), exhibits neuroprotective effects against the excitotoxicity implicated in the AD neurodegeneration. The present study investigates the effects of MSCs overexpressing VEGF in hippocampal neovascularization, cognitive dysfunction and senile plaques present in 2xTg-AD transgenic mice. MSC were transfected with vascular endothelial growth factor cloned in uP vector under control of modified CMV promoter (uP-VEGF) vector, by electroporation and expanded at the 14th passage. 2xTg-AD animals at 6, 9 and 12 months old were transplanted with MSC-VEGF or MSC. The animals were tested for behavioral tasks to access locomotion, novelty exploration, learning and memory, and their brains were analyzed by immunohistochemistry (IHC) for vascularization and Aβ plaques. MSC-VEGF treatment favored the neovascularization and diminished senile plaques in hippocampal specific layers. Consequently, the treatment was able to provide behavioral benefits and reduce cognitive deficits by recovering the innate interest to novelty and counteracting memory deficits present in these AD transgenic animals. Therefore, this study has important therapeutic implications for the vascular damage in the neurodegeneration promoted by AD.

Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine.

Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine.

Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice.

RATIONALE The endocannabinoid system has been implicated in the neurobiological mechanism underlying drug addiction, especially the primary rewarding dopamine-dependent processes. Therefore, endocannabinoid receptor antagonists, such as the CB1 cannabinoid antagonist rimonabant, have been proposed as candidates for preventive addiction therapies. OBJECTIVES Investigate the possible involvement of CB1 receptors in the development of behavioral sensitization to ethanol, morphine and cocaine in mice. METHODS We compared the effects of different doses of rimonabant (0.3, 1, 3 and 10mg/kg) on spontaneous locomotor activity in the open-field, hyperlocomotion induced by acute administration of ethanol (1.8g/kg), morphine (20mg/kg) or cocaine (10mg/kg) and on subsequent drug-induced locomotor sensitization using a two-injection protocol in mice. We also investigated a possible depressive-like effect of an acute rimonabant challenge at the highest dose and its potential anxiogenic property. RESULTS At the highest dose, rimonabant abolished ethanol- and cocaine-induced hyperlocomotion and behavioral sensitization without modifying spontaneous and central locomotor activity or inducing depressive-like behavior on the forced swim test in mice. The other doses of rimonabant also selectively blocked acute ethanol-induced central hyperlocomotion. Although rimonabant at 0.3 and 1mg/kg potentiated the central hyperlocomotion induced by acute morphine injection, it was effective in attenuating morphine-induced behavioral sensitization at all doses. CONCLUSIONS Because the neural basis of behavioral sensitization has been proposed to correspond to some components of addiction, our findings indicate that the endocannabinoid system might be involved in ethanol, cocaine and morphine abuse.

Bovine brain phosphatidylserine attenuates scopolamine induced amnesia in mice

This study verifies the effects of bovine brain phosphatidylserine (PS) on passive avoidance (PA) and contextual fear conditioning (CFC) tests in scopolamine-treated mice. Mice received daily i.p. 50 mg/kg PS or 0.2 M Tris pH 7.4 (TRIS) for 5 days. On day 6, mice received saline (TRIS-SAL and PS-SAL) or 1 mg/kg SCO (TRIS-SCO and PS-SCO) i.p. After 20 min, the animals were submitted to PA (experiment 1) or CFC (experiment 2) training sessions, and tests were performed 24 h later. Latency in entering the dark chamber of the PA apparatus presented by TRIS-SCO (but not PS-SCO) group in the test was significantly higher than those presented by controls. Except for TRIS-SCO, all the groups presented higher latencies in the test compared to the training session. In experiment 2, the TRIS-SCO (but not PS-SCO) group presented significantly lower freezing duration than that presented by the TRIS-SAL group in the test. Animals treated with PS alone presented higher freezing duration than that presented by the TRIS-SAL group. The results demonstrate that PS attenuates SCO-induced amnesia in both PA and CFC tests. In addition, PS per se improves retention in the CFC test.

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.

Amnestic effect of cocaine after the termination of its stimulant action

The effects of cocaine on memory are controversial. Furthermore, the psychostimulant action of cocaine can be a critical issue in the interpretation of its effects on learning/memory models. The effects of a single administration of cocaine on memory were investigated during the presence of its motor stimulating effect or just after its termination. The plus-maze discriminative avoidance task (PM-DAT) was used because it provides simultaneous information about memory, anxiety and motor activity. In Experiment I, mice received saline, 7.5, 10, 15 or 30 mg/kg cocaine 5 min before the training session. In Experiment II, mice were trained 30 min after the injection of saline, 7.5, 10, 15 or 30 mg/kg cocaine. In Experiment III, mice received 30 mg/kg cocaine 30 min pre-training and pre-test. In Experiment IV, mice received 30 mg/kg cocaine immediately post-training. Tests were always conducted 24 h following the training session. Given 5 min before training, cocaine promoted a motor stimulant effect at the highest dose during the training session but did not impair memory. When cocaine was injected 30 min pre-training, the drug did not modify motor activity, but produced marked amnestic effects at all doses tested. This amnesia induced by cocaine given 30 min pre-training was not related to a state-dependent learning because it was not abolished by pre-test administration of the drug. Post-training cocaine administration did not induce memory deficits either. Our results suggest that the post-stimulant phase is the critical moment for cocaine-induced memory deficit in a discriminative task in mice.

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.