Effects of sleep deprivation on memory in mice: role of state-dependent learning

Study Objectives:

A considerable amount of experimental evidence suggests that sleep plays a critical role in learning/memory processes. In addition to paradoxical sleep, slow wave sleep is also reported to be involved in the consolidation process of memories. Additionally, sleep deprivation can induce other behavioral modifications, such as emotionality and alternations in locomotor activity in rodents. These sleep deprivation-induced alterations in the behavioral state of animals could produce state-dependent learning and contribute, at least in part, to the amnestic effects of sleep deprivation. The aim of the present study was to examine the participation of state-dependent learning during memory impairment induced by either paradoxical sleep deprivation (PSD) or total sleep deprivation (TSD) in mice submitted to the plus-maze discriminative avoidance or to the passive avoidance task.

Design:

Paradoxical sleep deprivation (by the multiple platform method) and total sleep deprivation (by the gentle handling method) were applied to animals before training and/or testing.

Conclusions:

Whereas pre-training or pre-test PSD impaired retrieval in both memory models, pre-training plus pre-test PSD counteracted this impairment. For TSD, pre-training, pre-test, and pre-training plus pre-test TSD impaired retrieval in both models. Our data demonstrate that PSD- (but not TSD-) memory deficits are critically related to state-dependent learning.

Citation:

Patti CL; Zanin KA; Sanday L; Kameda SR; Fernandes-Santos L; Fernandes HA; Andersen ML; Tufik S; Frussa-Filho R. Effects of sleep deprivation on memory in mice: role of state-dependent learning. SLEEP 2010;33(12):1669-1679.     

Effect of paradoxical sleep deprivation and stress on passive avoidance behavior

Previous studies have shown that several types of stress can induce memory impairment. However, the memory effects of paradoxical sleep deprivation (PSD), a stressor in itself, are unclear. We therefore compared passive avoidance behavior of rats undergoing PSD and PSD stress yoked-control (PSC) using the "reversed flowerpot method." When rats were kept isolated on a PSC platform for 24 h immediately after criterion training, retention trials showed impaired aversive memory storage. When delayed for 24 h after criterion training, PSC stress did not disrupt retention performance. In rats subjected to PSD, either immediately or 24 h after criterion training, there was no disruption of aversive memory consolidation. These results suggest that, during stress, paradoxical sleep plays a role in erasing aversive memory traces, in line with the theory that we "dream in order to forget."     

Disruptive effects of rapid eye movement sleep deprivation on long-term memory

The fact that sleep is associated with very active endogenous neural (chemical and electrical) processes, suggests that these processes may be involved in the maintenance of long-term memory storage. The present experiments were designed to examine the hypothesis that rapid eye movement (REM) sleep deprivation will produce impairment of long-term memory. Mice deprived of REM sleep for 3, 5 or 7 continuous days, during the interval between a one-trial inhibitory avoidance training experience and a subsequent retention test, displayed a temporary retrograde amnesia when tested 30 min or three hr following termination of REM deprivation. The mice did not recover from the amnesia if electroconvulsive shock was administered immediately following the interval of REM sleep deprivation. In a further study, the generality of these findings was obtained by depriving mice of REM sleep during the interval between a discrimination training experiment in a black-white T-maze and the subsequent retention test.     

Retrograde amnesia: prolonging the fixation phase of memory consolidation by paradoxical sleep deprivation.

Mice given one-trial training in a passive avoidance task after 3 days of paradoxical sleep (PS) deprivation, and given electroconvulsive shock (ECS) at one of several intervals after training, display a protracted retrograde amnesia gradient on a retention test given 3 days later. ECS produces only a sharp gradient in comparable groups of animals that are not deprived of PS. The findings suggest that PS plays an important functional role in the processes that underlie the fixation of long-term memory.     

Modulation of memory processes induced by stimulation of the entorhinal cortex

This study investigated the effects of posttrial electrical stimulation of the entorhinal cortex in rats (3 mA or 300 microA; 60 sec, 3 hr or 6 hr after training) on retention of inhibitory or active avoidance responses. In the inhibitory avoidance task 3 mA, but not 300 microA, 60 sec after training produced retrograde amnesia. The 300 microA stimulation produced amnesia when given 3 hr after training, but 3 mA was without effect. Neither level of stimulation affected retention if given 6 hr after training. In the active avoidance task 300 microA given 60 sec and 3 hr after training significantly facilitated acquisition in comparison with unoperated, but not operated control rats. The 3 mA stimulation had no effect in the active avoidance task. Cortical afterdischarge activity occurred 64%, 23%, and 77% of the time when the 300 microA stimulation was given 60 sec, 3 hr, or 6 hr after inhibitory avoidance training, and 54%, 69%, and 92% for 3 mA. In the two conditions where amnesia was observed (3 mA at 60 sec and 300 microA at 3 hr) the lowest proportion of animals exhibited afterdischarge activity. Afterdischarge activity was not related to active avoidance performance.     

Dark avoidance learning and memory disruption by carbon dioxide in cockroaches

Cockroaches were trained to avoid the dark side of a box using electric shock as a negative reinforcement. The majority of the acquisition of learning occurred within the first minute of training. The reduction in the number of shock bouts initiated during training could be attributed entirely to avoidance learning; no evidence of escape learning was found. There was no decrease in retention of dark avoidance up to 2 hr after training. When carbon dioxide was administered immediately after training, no retention was observed 2 hr later. When CO₂ was given 1 hr after training some retention was observed 2 hr after training. These results indicate that memory phases which have different susceptibilities to disruption can be observed in cockroaches.     

Effects of cycloheximide on acquisition and retention of an avoidance learning in the rat: recovery of memory (author's transl)

Thirty minutes before an avoidance learning session in a Y maze, rats were given a subcutaneous injection of either cycloheximide (2,5 mg/kg) or saline. The animals were trained to a criterion of 4 or 8 consecutive avoidance responses. Retention tests were given 2 hr, 24 hr or 6 days after initial learning. The results show: (1) acquisition is not affected by the severe protein synthesis inhibition; (2) impairment of memory is found only in the low criterion experimental group 2 hr after learning and (3) in both experimental groups 24 hr after learning; (4) a recovery of memory is observed in both groups 6 days later. A control experiment indicates that the deficits found cannot be regarded as retrieval deficits. Transient amnesia is interpreted in terms of slowing down in long-term memory establishment process and this is thought to be due to a decrease in the rate of neurotransmitter synthesis.     

Paradoxical sleep deprivation applied two days after end of training retards learning

Sprague-Dawley rats (N = 98) were trained in a 2-way shuttle shock avoidance task (50 trials/day for two consecutive days) and then subjected to a paradoxical sleep deprivation (PSD) regime beginning at least 24 hours after the last training session. Results from the various PSD groups indicated that a vulnerable PS window exists from 48-72 hours after the end of the last training session. PSD during this time period produced severe retention deficits. These results suggest the existence of a very long term posttraining PS involvement in the learning/memory process.     

NMDA receptors are involved in Ginkgo extract-induced facilitation on memory retention of passive avoidance learning in rats

Herbal therapies are commonly used to enhance memory and learning. Ginkgo biloba has shown to be one of the most popular herbs that is used to treat amnesia and retard age related memory deficits. Although, there have been several reports on the memory enhancing effects of Ginkgo, involvement of glutamatergic system that plays pivotal role in learning and memory has not been precisely assessed so far. The current study intended to investigate the effect of Ginkgo intake on amnesia while NMDA (N-methyl D-aspartic acid) receptors blocked by the administration of MK-801. The study used passive avoidance (PA) task to investigate the effect of chronic administration of Ginkgo extract (40 and 90 mg/kg; oral) on the memory span in male Wistar rats, suffering from MK-801-induced forgetfulness (0.06 and 0.1 mg/kg; i.p.). The results indicate that Ginkgo was able to remove MK-801-induced forgetfulness, indicating that Ginkgo can affect memory retention but not effect on passive avoidance acquisition, using pathways other than glutamatergic system as well. The results might indicate that Ginkgo extract can be effective in removing forgetfulness caused by inhibiting NMDA receptors from performing their activities.     

Effects of protein synthesis inhibition on memory for active avoidance training.

Inhibition of brain protein synthesis by anisomycin and acetoxycycloheximide was studied in mice for its biochemical and behavioral effects. By employing both drugs in low doses in a series of injections, we were able to maintain inhibition of protein synthesis of 80% or greater for up to 14 hr without causing detectable permanent physiological impairment. The drugs were employed as amnestic agents in mice trained to avoid footshock in a T-maze. As the duration of inhibition increased, the percentage of mice classed as amnesic increased. This amnesia could be reduced by increasing (a) the rate of acquisition, or (b) the number of training trials. Anisomycin was shown to cause a significant degree of amnesia for the escape component as well as the avoidance component of the learning. A single injection of anisomycin given 15 min prior to training did not cause significant changes in the acquisition or retention of avoidance conditioning, when comparison was made with saline-injected controls. Only additional injections given after training to prolong inhibition caused amnesia. Thus, those injections critical in obtaining amnesia were given at a time at which interference with acquisition could not have occurred, so the results bear clearly on memory processes.     

Impairments of learned aversion acquisition following paraodixcal sleep deprivation in the rat.

The effect of paradoxical sleep deprivation (PSD) on taste-aversion learning was studied utilizing the classical water tank technique. When such a PSD was applied for 48 hr preceding and 48 hr following the learning session (LS), taste-aversion learning was completely abolished. A slightly attenuated effect was obtained when the entire 96 hr of PSD preceded the LS. When the 96 hr PSD followed the LS, learning was only slightly affected. The effect of PSD was duration dependant, starting at 7.5 hr pre-LS followed or not by the same duration of PSD post-LS. We conclude that this technique, thought to induce almost complete PSD in addition to nonspecific stress, affects particularly the acquisition processes (pre-LS PSD) and only slightly those of retention (post-LS PSD).     

Improvement of shuttle-box avoidance following post-training treatment in paradoxical sleep deprivation platforms in rats

The effects of post-training paradoxical sleep deprivation (PSD), via the platform method, on acquisition and long-term retention (LTR) of shuttle-box avoidance were studied in Wistar rats. Animals had a daily training session for 5 days (acquisition), following which each rat was placed for 5 hr either on a small platform (7 cm) surrounded by water (PSD group) or on a large platform (16 cm) surrounded by water (Yoked control group), or was given no treatment (Dry control group). Another identical training session (LTR test) was also given to every subject 14 days after the last acquisition session. The treatment on the large platform (Yoked animals) improved learning in successive training sessions. A similar but not statistically significant improvement was also observed in the PSD group. In the LTR test, the PSD animals tended to decrease performance as compared with the conditioning level achieved in the previous acquisition session. Locomotor and emotional changes produced by PSD and PSD procedures are ruled out as the cause for these findings. We suggest that arousal produced by both PSD and PSD procedures could have improved the acquisition of the conditioning, whereas PSD per se could have been detrimental for LTR of the learned response.     

Glucocorticoids are not responsible for paradoxical sleep deprivation-induced memory impairments

STUDY OBJECTIVES: To evaluate whether paradoxical sleep deprivation-induced memory impairments are due to release of glucocorticoids, by means of corticosterone inhibition with metyrapone. DESIGN: The design was a 2 (Groups [control, paradoxical sleep-deprived]) x 2 (Treatments [vehicle, metyrapone]) study, performed in 2 experiments: Acute treatment (single injection given immediately after 96 hours of sleep deprivation) and chronic treatment (8 injections, twice per day, throughout the sleep-deprivation period). Animals were either paradoxical sleep-deprived or remained in their home cages for 96 hours before training in contextual fear conditioning and received intraperitoneal injections of a corticosterone synthesis inhibitor, metyrapone. Memory performance was tested 24 hours after training. SUBJECTS: Three-month old Wistar male rats. Measurements: Freezing behavior was considered as the conditioning index, and adrenocorticotropic hormone and corticosterone plasma levels were determined from trunk blood of animals sacrificed in different time points. Animals were weighed before and after the paradoxical sleep-deprivation period. RESULTS: Acute metyrapone treatment impaired memory in control animals and did not prevent paradoxical sleep deprivation-induced memory impairment. Likewise, in the chronic treatment, paradoxical sleep-deprived animals did not differ from control rats in their corticosterone or adrenocorticotropic hormone response to training, but still did not learn as well, and did not show any stress responses to the testing. Chronic metyrapone was, however, effective in preventing the weight loss typically observed in paradoxical sleep-deprived animals. CONCLUSIONS: Our results suggest that glucocorticoids do not mediate memory impairments but might be responsible for the weight loss induced by paradoxical sleep deprivation.     

Age-related changes in visual recognition memory during infancy and early childhood

Age-related changes in long-term memory during infancy and early childhood were examined using the Visual Recognition Memory (VRM) procedure. Independent groups of 1-, 2-, 3-, and 4-year-olds were familiarized with a visual stimulus and were tested either immediately or after a delay that ranged from 24 hr to 6 months. Although all age groups exhibited a significant novelty preference when tested immediately after familiarization, clear age-related differences emerged over longer retention intervals. We conclude that age-related increases in basic retention are a fundamental aspect of mammalian memory development and, in humans, these increases may play a vital role in the offset of childhood amnesia.     

Sexual dimorphism in passive avoidance behavior of rats: Relation to body weight,age, shock intensity and retention interval

Female rats were inferior to age- and weight-matched males in the retention of a step-through type passive avoidance response 24 and 48 hr after the learning. This sex difference could be observed at different intensities of foot shock which was used as aversive stimulus during the single learning trial. Additionally, unlike in males, retention of the passive avoidance response in the females was not the function of shock intensity. Male and female rats, however, showed similar passive avoidance if tested immediately after the learning trial. The results suggest the existence of sexual dimorphism in memory processes.     

Reminder abolishes impairment of learning induced by paradoxical sleep retardation

Rats were submitted to one daily trial in a relatively complex maze. When sleep was delayed (by the water tank technique) for 180 min after each trial, learning was impaired. A reminder treatment (90 sec exposure to contextual cues) immediately before each trial, counteracted the effects of sleep deprivation. The reminder did not in itself contain sufficient information to facilitate performance of non sleep delayed animals. These results suggest that a retrieval failure is involved in memory impairment caused by post-learning paradoxical sleep deprivation.     

Effects of H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH on different behavioral tests of rats

Summary H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH inhibited the extinction of active avoidance behavior 3 h and 6 h after administration and facilitated the learning of a T-discrimination task. The peptide antagonized ECS-induced amnesia, if the treatment was performed 1h before the test session. These results suggest that H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH can facilitate learning and memory processes.     

Selective deprivation of paradoxical sleep and consolidation of shuttle-box avoidance.

Investigated whether paradoxical sleep is implicated in the storage of information acquired during shuttle-box avoidance. Wistar rats were given 5 brief training sessions distributed over the light period of the diurnal cycle. During the intervals between sessions the animals were selectively deprived of paradoxical sleep by awakening them every time they showed this type of sleep. The onset of paradoxical sleep was identified when hippocampal theta rhythm occurred during behavioural sleep. Yoked control animals got the same treatment irrespective of their sleep-waking behaviour, whereas free sleep rats were allowed to sleep undisturbed. In spite of large differences in the amount of paradoxical sleep during the intersession intervals no differences in learning performances were found among the groups. A tendency toward more intertrial crossings was noted in the paradoxical sleep deprived group at the end of training. It is concluded that storage of information acquired during distributed shuttle-box avoidance is not dependent on the presence of paradoxical sleep immediately following learning. Some possibilities are considered that paradoxical sleep may still be involved in memory storage processes.     

Correlations between paradoxical sleep and shuttle-box conditioning in rats

Eighteen male Wistar rats were given one daily two-way active avoidance conditioning session followed immediately by 5 hr of sleep recording, for 5 consecutive days. The group of rats that achieved 80% or greater avoidance in some of the 5 training sessions showed significant linear increases of paradoxical sleep (PS), compared with baseline levels, throughout the successive conditioning sessions. Furthermore, (a) the group of rats showing PS increases (more than 1 SD above baseline) after some of the training sessions achieved a significantly higher final number of avoidances than the remaining animals: (b) a high and positive correlation was observed between avoidance increases in the 3rd conditioning session and previous PS; and (c) maximum increases in correct performance often occurred following high PS increases. It is concluded that PS increases facilitate the consolidation of learning.     

Characteristics of retrograde amnesia following reactivation of memory in mice

Amnesia for approach-avoidance learning was induced in mice by injecting the protein synthesis inhibitor anisomycin (ANI) immediately, 1, or 2 hours, but not 3 hours after training. A robust amnesia could be demonstrated if ANI was administered 3 hours after training, immediately following a 60 second exposure to the training apparatus or to a structurally similar environment. The temporal gradient of effectiveness of amnesia production by ANI was significantly steeper following reactivation treatment than it was following initial training. In addition, while amnesia produced by the conventional procedure remained stable for 6 days, the amnesia induced following reactivation treatment spontaneously recovered 4 days after training. These findings are discussed in terms of their relevance to interpretations of retrograde amnesia studies.