Neuropsychopharmacological Induction of (Lucid) Dreams: A Narrative Review.

Lucid dreaming (LD) is a physiological state of consciousness that occurs when dreamers become aware that they are dreaming, and may also control the oneiric content. In the general population, LD is spontaneously rare; thus, there is great interest in its induction. Here, we aim to review the literature on neuropsychopharmacological induction of LD. First, we describe the circadian and homeostatic processes of sleep regulation and the mechanisms that control REM sleep with a focus on neurotransmission systems. We then discuss the neurophysiology and phenomenology of LD to understand the main cortical oscillations and brain areas involved in the emergence of lucidity during REM sleep. Finally, we review possible exogenous substances-including natural plants and artificial drugs-that increase metacognition, REM sleep, and/or dream recall, thus with the potential to induce LD. We found that the main candidates are substances that increase cholinergic and/or dopaminergic transmission, such as galantamine. However, the main limitation of this technique is the complexity of these neurotransmitter systems, which challenges interpreting results in a simple way. We conclude that, despite these promising substances, more research is necessary to find a reliable way to pharmacologically induce LD.

Coping with sleep deprivation: shifts in regional brain activity and learning strategy.

STUDY OBJECTIVES: dissociable cognitive strategies are used for place navigation. Spatial strategies rely on the hippocampus, an area important for flexible integration of novel information. Response strategies are more rigid and involve the dorsal striatum. These memory systems can compensate for each other in case of temporal or permanent damage. Sleep deprivation has adverse effects on hippocampal function. However, whether the striatal memory system can compensate for sleep-deprivation-induced hippocampal impairments is unknown. DESIGN: with a symmetrical maze paradigm for mice, we examined the effect of sleep deprivation on learning the location of a food reward (training) and on learning that a previously nonrewarded arm was now rewarded (reversal training). MEASUREMENTS AND RESULTS: five hours of sleep deprivation after each daily training session did not affect performance during training. However, in contrast with controls, sleep-deprived mice avoided a hippocampus-dependent spatial strategy and preferentially used a striatum-dependent response strategy. In line with this, the training-induced increase in phosphorylation of the transcription factor cAMP response-element binding protein (CREB) shifted from hippocampus to dorsal striatum. Importantly, although sleep-deprived mice performed well during training, performance during reversal training was attenuated, most likely due to rigidity of the striatal system they used. CONCLUSIONS: together, these findings suggest that the brain compensates for negative effects of sleep deprivation on the hippocampal memory system by promoting the use of a striatal memory system. However, effects of sleep deprivation can still appear later on because the alternative learning mechanisms and brain regions involved may result in reduced flexibility under conditions requiring adaptation of previously formed memories.

Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning.

Previous studies show that early life events result in neurobehavioural alterations that may be either beneficial or detrimental to the stress response. Given the close relationship between corticosterone secretion and mnemonic processes, the purpose of the present study was to investigate the effects of brief (BMS, 15 min) and long maternal separations (LMS, 180 min) on memory tasks in adult rats, assessed by context and tone fear conditioning. At adulthood, males were evaluated for behavioural and hormonal reaction to the training environment, being tested for context fear conditioning; tone fear conditioning; and learning curve in the context fear conditioning, in which rats were daily re-exposed to the context, followed by a brief footshock and in the last day of the experiment (day 5) animals were exposed to the context. Corticosterone and ACTH plasma levels were determined in naïve rats (basal) or 5, 25 or 45 min after each test. Peak ACTH and corticosterone levels were similar among the groups after context fear conditioning; however, levels of CTL rats remained elevated for a longer time. In the learning curve of context fear conditioning, both BMS and LMS rats exhibited less freezing behaviour than CTL rats, without differences in hormone secretion. There was neither an association between activity of the HPA axis and performance on memory tasks nor different activational properties of the tasks on the HPA axis between BMS and LMS rats, i.e., both manipulations lead to similar performance in hippocampus-dependent and independent memory tasks.

Corrigendum: Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with ß-adrenergic activity.

[This corrects the article on p. 51 in vol. 9, PMID: 25784866.].

Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with ß-adrenergic activity.

Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of ß-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals' performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals' performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of ß-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a ß-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a ß-adrenergic signaling.

Paradoxical sleep deprivation facilitates subsequent corticosterone response to a mild stressor in rats.

The pituitary-adrenal responsiveness to a mild stressor was assessed in rats that were deprived of paradoxical sleep (PS) and in controls that were not deprived. Animals were either individually- or group-deprived for 96 h and hormone levels were assessed at 0, 5, 20 or 60 min after a saline injection+novelty and compared with rats which were not deprived. Both types of PS deprivation resulted in elevated adrenocorticotropin levels at 0 min, which peaked at 5 min in all animals. Individually-deprived rats exhibited the highest corticosterone (CORT) levels at 0 min. Peak levels were higher and occurred earlier in PS-deprived than in control rats (5 vs. 20 min, respectively). At 20 min, CORT levels had already returned to unstressed levels in PS-deprived rats, but not in control rats. These data indicate that PS deprivation induces facilitation of the adrenocortical response to a mild stressor, but do not suggest that PS deprivation changes the negative feedback sensitivity to CORT.

Contextual exploration previous to an aversive event predicts long-term emotional consequences of severe stress.

Traumatic stress can lead to long-term emotional alterations, which may result in Posttraumatic Stress Disorder (PTSD). Fear reactions triggered by conditioned cues and exacerbated emotional arousal in face of non-conditioned stimuli are among the most prominent features of PTSD. We hypothesized that long-term emotional alterations seen in PTSD may depend on the strength of context-trauma association. Here, we investigated the contribution of previous contextual exploration to the long-term emotional outcomes of an intense foot shock in rats. We exposed male Wistar rats to a highly stressful event (foot shock, 2 mA, 1 sec) allowing them to explore or not the chamber prior to trauma. We, then, evaluated the long-term effects on emotionality. Fear was assessed by the time spent in freezing behavior either upon re-exposure to trauma context or upon exposure to an unknown environment made potentially more aversive by presentation of an acoustic stimulus. Behaviors on the elevated-plus-maze and acoustic startle response were also assessed. The possibility to explore the environment immediately before the aversive event led to differential long-term emotional effects, including a heightened freezing response to re-exposure to context, blunted exploratory behavior, fear sensitization and exacerbation of the acoustic startle response, in contrast to the minor outcomes of the foot shock with no prior context exploration. The data showed the strong contribution of contextual learning to long-term behavioral effects of traumatic stress. We argue that contextual representation contributes to the robust long-term behavioral alterations seen in this model of traumatic stress.

Lithium prevents REM sleep deprivation-induced impairments on memory consolidation.

BACKGROUND: Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. OBJECTIVE: To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. DESIGN: Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. SUBJECTS: Wistar male rats weighing 300-400 g. RESULTS: Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. CONCLUSION: Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained.

Stress during development alters anxiety-like behavior and hippocampal neurotransmission in male and female rats.

Epidemiological data indicate that early stress increases vulnerability to psychiatric disorders, including anxiety and depression. In the present study we sought to investigate the long-term behavioral and neurochemical consequences of increased and sustained corticosterone levels induced by a 24 h bout of maternal deprivation (DEP) imposed on postnatal day 11 (DEP11). As adults, animals were exposed to the elevated plus maze for assessment of anxiety-like behavior and corticosterone response to this challenge, or decapitated for determination of monoamines and amino acid neurotransmitters content in the hippocampus by HPLC method. The results showed that DEP11 male and female rats displayed increased time in the central hub of the maze and more risk assessment behavior, reflecting increased anxiety-like behavior; in addition, these animals continuously secreted corticosterone in response to the behavioral test until the latest time-point, e.g., 60 min post-stress. In males, maternal deprivation increased aspartate and glutamate levels and reduced taurine levels compared to non-deprived (NDEP) rats. DEP11 females displayed reduced noradrenaline, aspartate and GABA levels compared to NDEP counterparts. These results indicate that maternal deprivation at 11 days of age produced changes in hippocampal neurotransmission that may mediate the increased anxiety-like behavior observed in male and female deprived rats. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Disruptions of the mother-infant relationship and stress-related behaviours: altered corticosterone secretion does not explain everything.

The hypothalamic-pituitary-adrenal (HPA) axis is the main neuroendocrine system of response to stress, and an imbalance of this system's activity is believed to be at the core of numerous psychiatric pathologies. During the neonatal period, the glucocorticoid response to stress is maintained at low levels by specific maternal behaviours, which is essential for proper brain development. Effective evaluation of the impact of increased secretion of corticosterone during an essentially anabolic developmental period on adulthood behaviour involved separation of the neonate from its mother for periods ranging from 3 to 24h. It has been shown that disinhibition of the stress response is achieved by such procedures. The pioneering studies by Seymour Levine set the stage for a prolific and promising field of study that may help neuroscientists unveil the neurobiological underpinnings of stress-related disorders. Based on a series of studies, we propose that maternal separation and maternal deprivation change stress-related behaviours, but that corticosterone seem to be only partially involved in these changes in adulthood. It appears that extra-hypothalamic corticotrophin-releasing factor and neurotransmitter systems may be the primary mediators of these behavioural outcomes.