Neural Changes Developed during the Extinction of Cocaine Self-Administration Behavior
2011

Alejandro Higuera-Matas
Department of Psychobiology
School of Psychology
UNED
C/Juan del Rosal 1028040MadridSpain

Miguel Miguens email@example.com.
Department of Basic Psychology I
School of Psychology
UNED
C/Juan del Rosal 1028040MadridSpain

Nuria Del Olmo
Department of Pharmaceutical and Nutritional Sciences
School of Pharmacy
San Pablo-CEU University
Urb. Montepríncipe, Boadilla del MonteMadridSpain

Carmen García-Lecumberri
Department of Psychobiology
School of Psychology
UNED
C/Juan del Rosal 1028040MadridSpain

Emilio Ambrosio
Department of Psychobiology
School of Psychology
UNED
C/Juan del Rosal 1028040MadridSpain

Neural Changes Developed during the Extinction of Cocaine Self-Administration Behavior

Pharmaceuticals
4201110.3390/ph4101315Received: 8 September 2011 / Accepted: 20 September 2011 /Pharmaceuticals Review * Author to whom correspondence should be addressed; E-Mail: firstname.lastname@example.com (E.A.); OPEN ACCESS Pharmaceuticals 2011, 4 1316cocaine self-administrationextinctionneuroadaptive changes
The high rate of recidivism in cocaine addiction after prolonged periods of abstinence poses a significant problem for the effective treatment of this condition. Moreover, the neurobiological basis of this relapse phenomenon remains poorly understood. In this review, we will discuss the evidence currently available regarding the neurobiological changes during the extinction of cocaine self-administration. Specifically, we will focus on alterations in the dopaminergic, opioidergic, glutamatergic, cholinergic, serotoninergic and CRF systems described in self-administration experiments and extinction studies after chronic cocaine administration. We will also discuss the differences related to contingent versus noncontingent cocaine administration, which highlights the importance of environmental cues on drug effects and extinction. The findings discussed in this review may aid the development of more effective therapeutic approaches to treat cocaine relapse.

Introduction

While opiate and alcohol addiction may be partially treated with specific pharmacotherapies, no such approach is available for psychostimulant addictions [1]. Moreover, treatment of these disorders is further complicated by a high inherent risk of relapse. These features highlight the need for more effective prevention programs and a better understanding of the neurobiological mode of action of these substances with a view to developing drugs that aid patient recovery. Cocaine acts by blocking voltage-dependent sodium channels (which mediates its analgesic effects) [2] and inhibiting the reuptake of dopamine, serotonin and noradrenaline [3], acting presynaptically at the level of the vesicular monoamine transporter [4] and postsynaptically at M1 and M2 muscarinic receptors [5][6][7], serotoninergic receptors [8] and sigma opioid receptors [9]. Cocaine also exerts sympathomimetic effects, which appear to be mediated by its noradrenergic activity at the postganglionar terminals of the sympathetic autonomous nervous system. These effects include increased heart rate, mydriasis, vasoconstriction and salivation, gastric and pancreatic secretion. Increased noradrenergic activity in the locus coeruleus also mediates the increase in alertness and arterial pressure [2,[10][11][12].

A growing body of evidence suggests that the dopaminergic effects of cocaine are responsible for its psychomotor, rewarding and euphoric effects [13][14][15][16]. There is some controversy with regard to this issue as the reinforcing potency of cocaine was reported to be maintained in the absence of the DAT but decreased in the absence of the NET and its motivational rewarding effect was observed in the absence of the SERT, but not when both DAT and SERT are lacking [17]. However, impaired cocaine self-administration was more recently demonstrated in mice lacking the dopamine transporter [18].

From a neuroanatomic point of view, most of cocaine's rewarding and psychomotor activities appear to be dependent upon the integrity of the mesocorticolimbic dopaminergic system. Chronic cocaine intake is associated with functional alterations in specific neuronal populations within this circuit, as well as specific modulatory effects on neurotransmitter receptors, molecular signalling cascades and gene expression [19]. While much research effort in the last three decades has focused on cocaine's effects on the dopaminergic system, it should not be forgotten that this drug also affects the serotonin, noradrenaline, opioid, glutamate, GABA and corticotropin releasing factor (CRF) neurotransmitter systems (see below).

Mechanisms Involved in Cocaine Relapse

Relapse is one of the greatest barriers to the effective treatment of drug addiction. Craving and compulsive use of a drug are two central features of this phenomenon [20][21][22]. Two opposing theories have emerged to explain relapse. The first suggests that relapse occurs after activation of reward circuits, as observed following acute drug administration, which supports the existence of a proponent process [23,24]. An alternative hypothesis proposes the existence of an opponent process elicited by drug administration, which induces hypofunctionality in reward circuits that is ultimately translated to dysphoric states during drug withdrawal [25][26][27][28]. However, both theories fail to fully account for several relapse-related phenomena. For example, the opponent process theory is contradicted by the following observations: (1) periods of maximal drug self-administration do not always overlap with periods of maximal dysphoria, i.e., for a wide variety of drugs of abuse there is a poor correlation between drug withdrawal effects per se and drug craving [29]; (2) there is a large body of medical and experimental evidence indicating that the relief of withdrawal symptoms is not an effective method to treat addiction [23]; (3) passive drug administration to animals in which drug seeking has been extinguished reinstates this behavior [30]. These data suggest the existence of a drug craving mechanism independent of a negative reinforcement process. Taken together, this evidence suggests that the two core features of addiction (drug craving and relapse) are unrelated to the desire to escape the aversive consequences of abstinence.

The proponent process theory proposes a positive reinforcement process, yet it is similarly contradicted by several findings suggesting that positive reinforcement and hedonic states are not correlated. In the first place, several psychostimulant drugs that do not produce euphoria are still highly addictive, such as nicotine [31]. Moreover, drug intake is maintained despite the dysphoric states that may be associated with the initial phases of drug use and the negative consequences associated with long term use [23]. In addition, the intense pleasure that a drug may produce when administered acutely does not appear to be derived when the individual is exposed to environmental stimuli previously associated with the drug, although these stimuli can induce a robust relapse to drug seeking [30]. These observations point to a dissociation between the pleasure induced by acute drug administration and the desire to consume the drug. Finally, humans self-administer low doses of drugs that in themselves do not cause pleasure, as witnessed with cocaine and opiates [32]. Based on these and other findings, it is clear that neither of the two theories can fully explain the phenomenon of relapse. However, both theories suggest that drug abuse produces specific neural adaptations that mediate the intense craving and drug seeking behavior observed long after chronic drug intake. Chronic drug administration may induce two types of neuroadaptive changes. One such change occurs firstly as a direct consequence to the pharmacological effects of the drug and it may generate tolerance to the physiological effects of the drug. The second type of adaptation is derived from the strong associations between the reinforcing effects of the drug and the environmental stimuli associated with them. Hence, stimuli that are motivationally neutral may acquire the ability to elicit the same responses as the drug itself [33]. Considering the importance of such neural adaptations in drug craving and relapse, we will summarize the key findings of our group and other relating to the neural adaptations that occur during the extinction of cocaine self-administration.

Neural Changes Induced after the Extinction of Cocaine Self-Administration Behavior

The main experimental design we use in our studies involves a triad approach employing three groups of animals. The first group of animals can press a lever to obtain a drug infusion and thus, they can exercise contingent control on their self-administration behavior. The second group is yoked to the first and as such, the animals passively receive the drug whenever the rats of the first groups press a lever for an infusion. This group is used to control for the effects of contingency. The third group receives non-contingent saline injections and serves as a control for the pharmacological effects of the drug [34,35]. Using this basic design, we have analyzed the neural adaptations that occur after cocaine administration and during extinction (1, 5 and 10 days), when cocaine is substituted with a saline solution.

The Dopaminergic System

Using the design described above, we measured the levels of D1 and D2 dopamine receptors by quantitative autoradiography. The levels of D2-like dopamine receptors decrease in several forebrain regions after cocaine self-administration, an effect that is maintained throughout the extinction period. Interestingly, the long-term down-regulation of D2 receptors in cocaine-treated animals is more evident in self-administering rats than in yoked animals. Moreover, neither contingent access to cocaine nor passive administration of the drug affects dopamine D1 receptors in these experiments. These results are in agreement with previous reports in the literature. For example, chronic cocaine self-administration in monkeys leads to decreased binding level of D2 receptors in the anterior and central regions of the caudate nucleus, putamen, olfactory tubercle, and both the shell and core of the nucleus accumbens (NAcc) [36]. In the rat brain, a decrease in the binding levels to D2 receptor sites was also observed after withdrawal from limited but not extended access to cocaine, while D1 receptors were transiently up-regulated following 20 minutes of withdrawal [37].

Analysis of dopamine transporter (DAT) binding in these animals reveals an increase in DAT binding in the caudate-putamen (CPU), NAcc (core and shell) and ventral tegmental area (VTA) in response to contingent cocaine administration. Furthermore, when compared with saline and cocaineyoked animals, this increase in binding was maintained during the entire extinction period in most of the brain areas examined. These results are in agreement with previous findings that showed that the DAT up-regulation evident after cocaine self-administration endured after withdrawal [38]. There are, however, mixed results in the literature concerning the regulation of DATs after cocaine exposure and withdrawal. For example it has been shown that cocaine self-administration may lead to either decreases or increases in the number of DATs as a function of the self-administration phase. For example, the Porrino group showed that the DAT levels decreased after initial exposure to cocaine but increased with higher doses and after several self-administration sessions, moreover, these changes were region-specific [39]. In contrast, limited access to cocaine was shown to up-regulate DAT levels in another study, while extended access was ineffective in provoking such changes [40]. The reasons for the discrepancies may lay on the different species used in both studies (rhesus monkeys vs., rats), or the specific self-administration parameters used (number of sessions or session duration, for example). Other authors have found a significant up-regulation of the DAT following extended access and withdrawal, but these changes were restricted to the prefrontal cortex [20].

With regard to human cases, there are at least 10 postmortem studies that employed either in vitro binding or autoradiography techniques to evaluate and contrast the status of striatal DAT in cocaine dependence with matched healthy controls. The results of the studies are not consistent, with reports of significant increases, decreases, and no change in DAT in cocaine dependent subjects relative to controls (see [41] for a review).

It has been reported that DAT binding augmented and the expression of dopamine D2 receptors diminished after long-term chronic cocaine self-administration in monkeys [36,39,42]. Accordingly, we have found a decrease in D2 receptor binding that persisted even 10 days after the extinction [43].The coupling of increased DAT protein binding with a decrease in D2 receptor binding suggests an enhancement of dopamine transmission. In the absence of cocaine, increased DAT activity would lead to enhanced clearance of synaptic dopamine, thereby dampening dopamine neurotransmission.

However, no changes in basal extracellular dopamine levels have been reported in the NAcc after long term extinction of cocaine self-administration [44].

Chronic cocaine self-administration also decreased tyrosine hydroxylase (TH-the rate-limiting enzyme for dopamine synthesis) protein levels in the NAcc shell (but not core) after one week of withdrawal from self-administration [45]. In contrast, repeated extinction training during a one week withdrawal period completely normalized deficits in TH to levels found in untreated controls [45]. This same group reported that TH levels in VTA dopamine neurons were not altered after one week of withdrawal from chronic cocaine self-administration [45]. However, extinction training during withdrawal increased TH in the VTA over control levels. Thus, in both VTA and NAcc, extinctioninduced regulation represents an increase in TH relative to animals control animals without extinction training. These results suggest that normalization of TH deficits in the NAcc could result from an increased TH synthesis in the VTA leading to greater transport to dopamine terminals in the NAcc. Alternatively, extinction training could stabilize or impair degradation of TH in dopaminergic terminals of the NAcc shell; see [46] for an interesting review on this issue.

The Glutamatergic System

In addition to the changes reported in the dopaminergic system, NMDA glutamate receptor expression is altered 1 day after the extinction of cocaine self-administration. This change is shortlived and no such changes are observed 5 or 10 days after extinction. Furthermore, this cocaineinduced modulation is dependent upon the mode of cocaine administration and while NMDA receptors augment in animals that self-administer cocaine, they decrease in those receiving yoked infusions (unpublished observations). When expression of the NMDAR1 subunit of the NMDA receptor was assessed, it increases in forebrain regions involved in the cocaine-reinforcing effects of the noncontingent group during cocaine administration and subsequent extinction. Similar alterations in NMDAR1 mRNA are observed in all the brain areas analyzed, although the magnitude of the changes vary in each brain region and in function of the mode of cocaine administration (contingent versus non-contingent). Across the brain, NMDAR1 gene expression is upregulated by contingent cocaine administration on the last day of drug intake when compared with saline or non-contingent cocaine administration. In the absence of cocaine in the contingent group, NMDAR1 mRNA expression decreases progressively, an effect that persists for up to 10 days after extinction in all forebrain areas except the olfactory tubercle (TU). By contrast, non-contingent cocaine administration does not change NMDAR1 gene expression on the last session of cocaine intake, while drug withdrawal in this group increases the NMDAR1 mRNA transcripts on Days 1 and 5 of extinction. However, this increase returns to the basal (saline) level 10 days after the last non-contingent drug administration session. These results suggest that interaction between environmental stimuli and the pharmacological action of cocaine during self-administration and extinction is important for cocaine-mediated regulation of NMDAR1 gene expression. Furthermore, the sustained decrease in NMDAR1 mRNA 10 days after extinction in the contingent cocaine group is not consistent with a response to short-term compensatory adaptations in brain function in the forebrain region [47].

Other groups have found that extinction training increases the amount of GluR1 and GluR2/3 subunits of AMPA glutamate receptors in the NAcc shell subregion [48]. In contrast to GluR1 and GluR2/3, the NR1 subunit of NMDA receptors decreased in the NAcc shell after one week of withdrawal from chronic cocaine self-administration. However, extinction training prevented deficits in NR1. This effect also required access to the response levers, and hence, extinction of cocaineseeking instrumental responses. These results are opposed to those previously reported by us (see above) and several methodological reasons, such the number of self-adminstration or extinction sessions, or the technique used to measure NR1 levels (Western blot vs. in situ hybridization) may account for these discrepancies. The extinction-induced changes in GluR2/3 and GluR1 content have functional consequences on extinction behavior and subsequent relapse. In this sense, it has been shown that viral-mediated GluR2 and GluR1 overexpression in the NAcc shell facilitates extinction and attenuates reinstatement [48].

Extinction training after cocaine self-administration has also been shown to induce glutamatergic plasticity to inhibit cocaine seeking [49]. In this study, rats were either extinguished or withdrawn without extinction training from cocaine self-administration, and measurements of postsynaptic density proteins in the core and shell subcompartments of the NAcc were compared with yoked-saline controls. Only extinguished rats had elevations of PSD-95, Homer1b/c, and Narp in the postsynaptic density of the NAcc core, with no changes in the shell. The authors also reported that surface expression of mGluR5 was reduced only in the core of extinguished animals, suggesting that that the elevation in Homer1b/c in the core may have sequestered mGluR5 away from the membrane surface and that the loss of surface mGluR5 could have inhibited long-term depression. This could be a cellular mechanism that may contribute to the inhibition of cocaine seeking after extinction of the selfadministration behavior [49].

Glutamate levels are controlled by the excitatory aminoacid transporters (EAATs). We observed changes in glutamate transporters after cocaine self-administration and subsequent extinction. We detected a decrease in binding to EAATs, the family of glutamate transporters, in the CA1 subfield of the hippocampus and the cerebellar cortex after chronic cocaine self-administration. By contrast, binding to EAATs increases after extinction of this behavior for 1 day, but only in the infra-limbic portion of the medial prefrontal cortex. No other differences in EAAT binding levels were observed in any of the brain regions analyzed. However, it should be noted that the radioligand used in this study could not differentiate between the different subtypes of EAATs involved in glutamate transport and thus, changes in the expression of a particular EAAT subtype could be masked by the expression of another subtype. Interestingly, the neuroadaptive changes in EAAT binding were only detected in animals receiving contingent cocaine administration, in accordance with the differential neurochemical effects in response to contingent versus non-contingent cocaine administration described elsewhere [47,50,51]. Notably, these changes in EAAT binding were reversible, as they were no longer detected after 5 or 10 days of extinction.

In another study we set out to define the time course of the effects of cocaine self-administration and extinction on glutamate and aspartate levels in the NAcc. Rats were trained to self-administer cocaine for 20 days, and the levels of extracellular glutamate and aspartate measured by in vivo microdialysis during cocaine self-administration and after a priming cocaine injection at different time points after extinction (1, 5, or 10 days). A food-reinforced control group was also included in the study. In addition, we evaluated the effect of acute i.v. cocaine administration (0, 1, 2, or 4 mg/kg) on glutamate and aspartate levels. We found that at all doses tested, acute i.v. cocaine has no effect on the levels of glutamate or aspartate in the NAcc. By contrast, glutamate levels are reduced in animals trained to self-administer cocaine, although substantial increases are evident during a subsequent session of cocaine self-administration and no such effects are observed in food-reinforced controls. After 1 or 5, but not 10 days of extinction, glutamate levels are reduced. The ability of i.v. cocaine priming injections to increase glutamate levels followed a similar time course, and these effects were specific, as aspartate levels are not affected by any administration protocol. Taken together, these results suggest that recent chronic cocaine administration is necessary to reduce basal glutamate in the core of the NAcc, and that glutamatergic transmission is involved in both the maintenance of cocaine self-administration and the early phases of abstinence [52].

Glutamatergic and dopaminergic transmission are intimately associated with plastic processes such as long-term potentiation (LTP) [53,54]. As such, we analyzed the status of LTP in the hippocampus of rats after extinction of cocaine self-administration. In hippocampal slices from animals in which chronic cocaine self-administration behavior was extinguished, high frequency stimulation evokes greater LTP than that observed in animals that self-administered saline. Thus, cocaine selfadministration appears to induce long-lasting changes in hippocampal synaptic plasticity that are maintained 10 days after the last self-administration session. While the mechanisms involved in this facilitation of LTP remain unknown, it is tempting to speculate that chronic self-administration of cocaine induces enduring metaplasticity in the hippocampus, facilitating neuronal responses to stimuli such as a single tetanus spike. In addition, our data suggest that neuroadaptive changes in hippocampal synaptic transmission play an important role in the long-term addictive potential of cocaine [55].

The Opioidergic System

To analyze the endogenous opioid system, we studied the effect of long-term self-administration of cocaine and its subsequent extinction on PENK gene expression in the CPu, NAcc, Tu, piriform cortex (Pir), central nucleus of amygdala (Ce) and ventromedial hypothalamic nucleus (VMN). The magnitude and significance of the changes in PENK gene expression vary, depending on the brain region examined and the mode of drug administration (contingent versus non-contingent). Both contingent and non-contingent cocaine administration increase the expression of PENK on either the last day of cocaine self-administration or during extinction in all the brain regions examined, with the exception of the VMN and Ce nuclei where significant decreases were detected in contingent animals when compared to non-contingent and control animals. In the VMN, the decrease in PENK gene expression returns to basal levels 10 days after the extinction of cocaine self-administration behavior, while this decrease is maintained in the Ce for the entire 10-day period of extinction. These sustained effects on PENK gene expression do not suggest a response to short-term compensatory adaptations in brain function after cessation of cocaine self-administration. Interestingly, our results reveal important differences in PENK gene expression in some brain regions that depend upon the mode of cocaine administration. Although PENK mRNA expression differs in most brain regions of the animals that received cocaine, with the exception of VMN, the changes persisted mainly in the cocaine contingent administration group 10 days after extinction. These results suggest that the interaction between environmental stimuli and the pharmacological action of cocaine during drug self-administration and extinction may represent an important variable in cocaine-mediated regulation of PENK gene expression [51] which could also have important implications for the regulation of relapse into cocaine seeking [56].

The CRF System

Given the growing importance of CRF transmission in addiction [26,57], we considered it essential to analyze CRF expression in our experimental model [50]. Accordingly, we demonstrated that CRF gene expression is altered in the paraventricular nucleus (PVN) of the hypothalamus, whereby longterm cocaine self-administration and extinction provoke a large concentration of neurosecretory CRF cells. As observed for other neurotransmitter systems, the mode of cocaine administration appears to be an important variable in regulating CRF gene expression in the PVN. While long-term cocaine selfadministration has no effect on CRF mRNA expression in the PVN, passive cocaine administration in yoked subjects dramatically reduces CRF expression. In our experimental design, animals that selfadminister cocaine can regulate and control their own cocaine intake, whereas the yoked cocaine administered animals have no such control over their intake. Thus, these results suggest that environmental events associated with cocaine self-administration may play an important role in mediating the effects of cocaine on hypothalamic CRF mRNA expression.

The Cholinergic System

As stated in the introduction, cocaine acts postsynaptically at the level of M1 and M2 muscarinic receptors and therefore, neural adaptation of these receptors may occur during cocaine selfadministration and extinction. Indeed, muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Consequently, an attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation has been recently reported [58]. Additionally, M2 receptors in the lateral dorsal tegmental area modulate cocaine reward as M2 agonist infusions in the lateral dorsal tegmental area reduced cocaine self-administration [6]. In addition, activation of muscarinic and nicotinic acetylcholine receptors in the NAcc-core is necessary for the acquisition of drug reinforcement [59]. When we analyzed the levels of M1 and M2 receptors in the three groups of animals used in our experimental paradigm, contingent cocaine administration augments the muscarinic receptors in the forebrain (cingulate cortex and other regions). Interestingly, these changes were not evident in other caudal regions, such as the VTA and the caudal mesencephalon, although non-contingent cocaine administration augments the muscarinic receptors found in these regions, as well as in the NAcc. In limbic areas such as the hippocampus, both contingent and non-contingent cocaine administration decrease the levels of muscarinic receptors. These changes remain stable throughout the extinction period, highlighting the enduring nature of neural adaptations in the cholinergic system induced by cocaine self-administration [60]. These results are consistent with the fact that cocaine priming-induced reinstatement is mediated, in part, by increased signaling through muscarinic acetylcholine receptors in the shell subregion of the NAcc [61]. The literature regarding the role of muscarnic receptors on human cocaine addiction is rather scarce. There is one report providing evidence for altered neural cholinergic receptor systems in cocaine-addicted subjects. In this work, it was shown that cocaine addicted subjects and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory [62]. Therefore, it can be suggested that cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

Conclusions

The data presented above suggest that cocaine self-administration modifies a number of neurotransmitter systems that might influence susceptibility to relapse. In particular, a divergence can be seen in the effects of contingent versus non-contingent exposure to cocaine, which serves to highlight the importance of goal-directed behavior in mediating the neuromodulatory effects of cocaine. Another important observation is the persistence of the neuroadaptive changes in regulatory elements of the dopaminergic, opioidergic and cholinergic systems during the extinction period. Hence, long term adaptations in these neurotransmitter systems play an important role in the relapse phenomenon, representing potential pharmacotherapeutic targets to deal with cocaine addiction.
 © 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
AcknowledgmentsThese studies were supported by the Ministerio de Ciencia e Innovación (SAF2007-064890); the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III: RD06/001/0029 and Plan Nacional sobre Drogas 2008-2010); the Dirección General de Investigación de la Comunidad de Madrid (S-SAL/0261/2006; Consorcio I+D CANNAB-CM); and the UNED (Plan de Promoción de la Investigación). We would like to thank all the past and present members of the Psychobiology of Drug Addiction lab for their work and insight, all of which has made this review possible.Conflict of InterestThe authors have no conflicts of interest to declare.
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Effect of a short rest period on associative and relational memory performance: A Virtual Reality study
2020

N Ribeiro
C Sagnier
V Quaglino
Y Gounden
E Loup-Escande
Effect of a short rest period on associative and relational memory performance: A Virtual Reality study

International Journal of Virtual Reality
20202010.20870/IJVR.2020.20.1.3186Received: 1/2020Effect of a short rest period on associative and relational memory performance: A Virtual Reality study. International Journal of Virtual Reality, 20(1), 21-32. CC BY 4.0 licenseMemory -Associative -Nap -Virtual Reality -Cognition
Virtual reality immerses individuals in 3D environments where spatial properties are similar to those of real life. Virtual reality can therefore be effective and relevant in the study of memory processing, especially when spatial properties are involved. We studied the effect of a 20-minute rest period on memory performance for associative and relational learnings. Eighty-one participants were placed in a virtual environment in which they learned 24 associations implicating objects and their respective precise location. As expected, the performance of associative memory was improved by a rest period between study and test phases. We discuss these results and the benefits of using an immersive virtual environment for such memory investigation. In addition, elaborating our environment was highly informative and led to several recommendations that we believe could be useful for researchers who would like to rely on virtual reality for investigating memory.

Introduction

When human beings evolve in a 3D world, most of their experiences are spatialized. Being able to encode, store and retrieve the spatial properties of what we experienced is important for adaptability to our environment and is a key feature of episodic memory. In addition, the integration of the spatial components of the experience in long-term memory is enhanced by a period of rest and/or sleep (Orban et al., 2006;Rauchs et al., 2008). However, in a research context, spatialized memory tasks that are presented on 2D screens can reasonably be considered far removed from typical real-life situations, especially in terms of spatiality. Virtual reality (VR) allows researchers to present three-dimensional objects in specific positions in a manner similar to reality while providing the same experimental control as one offered by other digital technologies (Sauzéon et al., 2012). The presentation of a memory task with a spatial component has been facilitated by the fact that virtual reality headsets have become more affordable and reliable (Smith, 2019). The elements we encounter in our daily lives are not memorized in isolation. Indeed, the way in which these elements are associated and related to each other is decisive for memory performance. Moreover, the sleep (a full night and a day nap) is posited to benefit on many aspects of cognition and specifically to memory (Rasch & Born, 2013;Ficca et al., 2010). For instance, Lahl et al. (2008) demonstrated that sleep benefits in general memory for naps as short as 6 minutes. More specifically, sleep improves performance for both the associative and relational properties of memory (Rasch & Born, 2013). For example, when the spatial properties of an episode are reactivated in the hippocampus, these reactivations are supposed to contribute to the consolidation of the whole memory (Talamini et al., 2008). This associative and relational improvement has been studied over periods ranging from twenty minutes of offline delay (delay without rehearsal) to several days with a typical sleep-wake cycle (Ellenbogen et al., 2007). To our knowledge, memory improvement for specifically associative and relational performance has not yet been demonstrated for a period of 20-minutes or less using VR design. Our study aims at evaluating the effect of a 20-minute rest period with a nap, on the memory performance for associated and related items (also referred as object in this study), using an associative inference task in VR.

Memory: Main concepts

Memory relies on how our brain changes in response to experience (episode). Properties of these episodes are not stored in separate boxes but are associated. For instance, when one eats a lemon, its color, shape, taste and the context of the situation are directly associated in memory. Additionally, an episode is also integrated in our memory in relation with experience preexisting in the system. These relations are also referred as inference as they rely on content similarities inferred by the system. For instance, if a candy packaging ostensibly shows a lemon on its packaging, it is likely that a relation is form between lemon properties (such as its sourness) and the candy. In the present study, the term associative memory will refer to the links that are directly created in memory when different perceptive elements or information are presented at the same time in our environment. For instance, when an image is presented at a specific location on a screen there is an association created in memory between the location and the object. The term relational memory will refer to the links that exist in memory between different elements that were ever directly presented at the same time but are related by a content similarity. For instance, two objects that were presented in the same location on a screen at different time are indirectly related in memory through their common location. Consideration for such associative and relational processes can be traced back to the beginning of experimental psychology, for instance Baldwin (1893, p. 162) indicated already how the complex network of interconnected brain cells can support diverse and related memories. Across the last century, consideration for such associative properties of memory has been sophisticated to consider how associated memory traces are likely to be related depending on the similarity they share (Eichenbaum, 2004;Hebb, 1949). The recent memory models, such one of Versace et al. (2014), rely mainly on such associative and relational principles. The Act-In model proposes two dynamics called activation and integration. During a perceptual experience, the components of the experience being lived propagate in memory and activate previous traces in the memory network according to the similarities they share with these components. The separate components are then combined into an episodic trace through the progressive integration of newly activated traces with related pre-existing ones. In this study, the associative properties of memory will refer to how two elements that share common features (such as the location, component, time, etc.) are linked in memory when they are experienced by an individual. Relational properties will refer to the inference that arises from distinct associations that share a similar element (in this study, a similar location inside the environment). Another example of this type of association and relation in everyday life might be when a person looks for his or her keys and finds them under the cushions of his or her couch. With this example, a location and an object are associated with memory. The next time the person loses his or her keys, it is likely that the memory of the couch episode will be automatically retrieved. Such association can also help to form a relational inference. For example, if this person is invited to a friend's house and can again no longer find his or her keys, he or she could easily infer that they may be hiding under the cushions of that friend's couch. In other words, associative and relational properties of memory allow characteristics associated with specific situations to be automatically transferred to a new situation that share similarities. These aspects of memory have been investigated principally during the wake period. However, as human consciousness varies throughout the day, they were also studied with an interest in sleep (Rasch & Born, 2013). This study is being conducted as part of these efforts to better understand how memory performance and sleep interact.

Sleep, nap and Memory performance

How sleep influences memory has been scientifically investigated in different memory processes or systems for more than a century (for a review, see Rasch & Born, 2013). Sleep has also been found to positively influence several components of memory such as procedural motor activities (Walker et al., 2003), procedural spatial memory (Talamini et al., 2008), semantic integration of nonwords (Tamminen et al., 2013) and episodic memory (Inostroza & Born, 2013;van der Helm et al., 2011;Wiedemann, 2007). In a systematic review, Chatburn et al. (2014) indicated that sleep facilitates the memory processing underlying associative performance in normal adult populations. In a theoretical review based on the Act-In model, Cherdieu et al. (2018) also indicated how sleep promotes the binding of associated elements leading to the emergence of new knowledge based on the components that are incorporated. Ellenbogen et al. (2007) demonstrated specifically how relational memory develops during offline time delays (a period without further training) using a transitive inference task. Precisely, they tested the effect of a 20-minutes offline delay and found no significant effect on memory performance. Additionality, an increase of relational memory performance was demonstrated for a 12-hour delay that included sleep compared to a 12-hour delay that did not included sleep. Finally, a 24-hour delay which included a normal sleep schedule also exhibited performance enhancement at relational levels. Alger and Payne (2016) developed a version of the associative inference task and tested the effect of sleep on the memory performance of their participants. This task allows the evaluation of both associative and relational properties of memory. Their study showed that associative and relational performance can be increased after a 90-minutes sleep opportunity. It is not yet known whether the associative performance can specifically benefit from a shorter sleep period.

Virtual Reality and Memory

To our knowledge, all the studies that have investigated the links between naps and memory performance with regard to its associative and relational properties have used a computer task that presented on the same screen, the elements that were to be associated. The use of a computer is widely used and accepted as an effective way to present multiple items while controlling presentation time, contrast constraints, allowing randomization of the order of presentation of items, etc. (Naus et al., 2009;Schatz & Browndyke, 2002). Recently, VR solutions have become more affordable, accessible and reliable (Bohil et al., 2011). The possibilities offered by these technologies are interesting because the use of a two-dimensional computer screen can reasonably be considered far removed from what individual encounters when associating the events that occur in his or her daily life in a dynamic three-dimensional world. Concerning the associative and relational properties of memory, Robin and Olsen (2019) have shown that associative performance is better when a scene is proposed. Additionally, a task that proposes an environment in which the participant can move around is likely to influence oneiric mentation and therefore improve performance (Wamsley & Stickgold, 2018;Wamsley et al., 2010). The use of VR appears to be a good strategy for both providing a complex environment or scene and allowing the participant to move freely in a 3D space.

Aims and hypothese

The present study aims at evaluating the effect of a short rest period on associative and relational performance on a memory task proposed in virtual reality. We expect that participants in the rest group will recall more correct associations and relations than participants in the wake group.

Methods

Participants

82 undergraduate students from Picardie Jules Verne University (48 women, 36 men; M = 21.63 years, age range: 19-26 years) were enrolled on a voluntary basis in this study. Prior to entering the protocol, all participants signed a consent form indicating the main goal of the study, the time required to complete the study, the possibility of requesting the deletion of their data, the exclusion criteria (no sleep trouble) and the anonymization of all data used in communication. Participants were informed that they should stop the experiment if they experienced symptoms of cybersickness. Only one participant reported transient dizziness and stopped the experiment. Using the random distribution, participants had a one-in-three chance of being in the wake group; the others were included in the rest group. This repartition was chosen to maximise the chance to have enough participants that slept in the rest group.

Material and Measures

The headset used in this study was an HTC Vive displaying 1080x1200 pixel for each eye. This headset yields a 100° horizontal field of view with a refresh rate of 90 Hz. It was connected to an HP ZBook 17 G3 with an Intel Core i7 (Quad-Core 2.6 GHz / 3.5 GHz Turbo), 8 GB RAM and a NVIDIA Quadro M5000M graphic card. The environment was developed using Unreal Engine 4 (UE4).

3.2.1. Associative Spatialised Memory Room During a pre-test, some participants looked surprised when they took off the headset and indicated that this surprise was probably due to the unexpected difference in size between the real test room and the virtual environment. As we did not know whether this surprise would affect the study or not, we decided to reduce this difference by matching the size of the rooms and placing a door in the same place. In the environment, 12 display stands were disposed in front of the participant, 4 at the left side, 4 at the back side and 4 at the right side. Each display stand was covered to only show the item when the participants pressed a button placed on the stand. For each revelation, a luminous mark on the button indicated which display stand was to be opened. By pressing the button with a standard controller, the participant would hear a clicking sound. The room was illuminated using an omnidirectional light source placed in the middle of display stands. A black cross was drawn on the floor to indicate to the participant where he or she needed to go after each item reveal. During the associative recall, a supplementary display stand was shown in the center of the room to display the item for which the participant had to indicate the location. A laser pointer was available and movable by the participant to indicate which stand he or she had previously seen the item displayed.

3.2.2.Items Selection

The items, also referred as object in this study, were selected from 3D models proposed online on the Unreal engine market and other websites with a CCO or CC BY license. Two pre-test sessions were conducted with undergraduate students, a PhD student specialising in VR, a professor of neuropsychology, and a research engineer in order to ensure good readability of the items and environment, to maximise the items uniqueness, and to avoid phobogenic items. Out of 41 3D models, 25 were selected and another one was randomly excluded to fit the final 24-items list composed of: Green plant, Computer, Spray can, Sledge, Car, Cactus, Gift box, Rock, Camera, Stool, Ball, Mushroom, Hat, Toilet, Pumpkin, Fire extinguisher, Violin, Dice, Bread, Hammer, Crow, Fish, Saw, Armchair. The graphic appearance of the objects was preferably chosen for the realistic and compatibility with an accurate representation of the object (as opposed to stylized or cartoonish). However, as the models came from different authors, the graphics identity were certainly not identical between the objects. A figure presenting the objects is available on request to the corresponding author of the present article (to ensure the novelty of the objects in the context of future studies).

3.2.3.Scores composition

Each correct recall granted the participant 1 point. Scores for immediate free recall, delayed free recall, immediate associative recall and delayed associative recall were integers (min = 0/24, max = 24/24). Score for relational recall was integer (min = 0/12, max = 12/12).

3.2.4.Subjective Evaluation of Sleep and Actimetry

All participants completed an additional two-part questionnaire (20 minutes after the task and 40 minutes after the task). Participants in the rest group were asked whether or not they had slept, how long they estimated their nap and whether or not they had dreamt during this short sleep. All participants in the rest group were tracked by actimetry using an Actiwatch 2 (Rupp & Balkin, 2011). Actimetry limited the possibility of a Type 1 error (indicating that one is asleep when one is not). Data from 8 of the 55 participants in the rest group were not recorded by the watch because of a failure in memory management by the researcher. However, all participants who reported being asleep were monitored.

Procedure 1

Participants were placed in the virtual environment. For the learning task, each participant was instructed for each association, to stand on the black cross and identify the display stand with the luminous marker. They were then requested to go to the display and open it by placing his or her hand on the button. The participant proceeded in the same way for the next display. Participants performed the recall task while starring at the back wall. The instruction for free recall test was to indicate aloud which objects were seen in the learning phase. The instruction for associative recall was to indicate the display stand containing the object using the laser. Finally, the instruction for relational recall test was to indicate aloud which object had the same position as the object displayed in front of the participant. During this relational recall, participants were placed in a circular room to ensure that spatial cues from the environment were not used to infer the relationships. The figure 2 depicts what was asked to the participant during each learning phase. The figure 3 and 4 illustrate the associative recall phase and the relational recall phase.   During the delay at the end of the learning, part of the sample was placed in the rest group in which they were offered a 20-minute nap window in a quiet room and the other part of the sample was placed in the wake group in which they were asked to continue their daily routine for 20 minutes. Afterwards, all participants were given a 20-minute delay prior to the delayed recall. The procedure is summarised in figure 5.

Results

All statistical significance thresholds were set at p < .05. In this section, we first studied the group effect by comparing those who were offered a nap (rest group) to those who were asked to continue their daily routine (wake group). We then studied a group effect by comparing only participant in the rest group based on whether or not they reported having a nap (verified by actimetry).

Main results

To compare the two groups (rest and wake), we performed two repeated-measures ANOVAs. Firstly, a repeated-measures ANOVA was performed on free recall score. The condition (rest or wake) was used as a factor between subjects and type of delay (immediate/delayed) was used as a factor within subjects. There was a significant effect of delay type (F (2, 80) = 98.99, p < .001), and no significant interaction effect (F (2, 80) = 6.26, p = .015). Secondly, another repeated-measures ANOVA was performed on the associative recall score. The condition (resting or wake) was used as a factor between subjects and type of delay (immediate/delayed) was used as a factor within subject. There was a significant effect of recognition type (F (2, 80) = 17.31, p < .001), and a significant interaction effect (F (2, 80) = 9.78, p = .002). Additionally, following the method employed by Alger and Payne (2016), we computed delta scores (dScore) by subtracting performance of immediate recall to delayed recall for the free and associative recalls. The t-test comparisons yield similar outcomes of the ANOVAs: dScore for free recall in the rest group ( M = 1.35, SD = 2.59) and in the wake group (M = 2.50, SD = 3.20) were not significantly different (p = .078, Cohen's d = -.41); dScore for associative recall in the rest group (M = 2.41, SD = 1.88) and in the wake group (M = 1.70, SD= 2.32) were significantly different (p = .002, Cohen's d = .71). The aforementioned results are summarised in Figure 6. A student t-test comparing the two groups for relational recall score was not significant. In the rest group, 27 participants out of 54 reported sleep. All 27 shown actimetry consistent with sleep. Using a Student's t-test, we compared participants who slept and those who did not for all performance indicators (immediate and delayed free recall, immediate and delayed associative recall, and relational recall); no comparisons were significant. Using a Spearman correlation analysis, we assessed if the time spent sleeping was correlated with performance; no correlation was significant. We performed again the two ANOVA (Wake, Rest) while keeping only in the rest group, participant who had not slept (n = 27) for a comparison and those who had slept (n = 27) in another comparison. The significance outcomes were identical as those displayed in figure 1 suggesting that sleep did not influence significantly our result.

Discussion

In the present study, we elaborated an associative inference task (Alger & Payne, 2016;Huguet et al., 2019) that allows the evaluation of associative and relational properties of memory. One of the originalities of this study was to use the possibilities that offer virtual reality (VR) to form association between an object and a location in a space room. Another originality was to investigate the effect of a short period of rest and the possible nap that took place within this period of associative and relational performances. The main results of the present study concerned the enhancement of associative recall after a nap opportunity which is consistent with precedent research (Alger & Payne, 2016). Most of our results are congruent with the state of art in the literature as, on the one hand, associative performances were better for the participants who had a period of rest than for the other participants. In another hand, relational performances were not different between groups as previously observed by Ellenbogen et al. (2007) who proposed that relational enhancement may depend on an offline process that needs more than 20 minutes to be perceptible. Another explanation could be found in the intentionality of learning. In this study, we did not inform the participant that he or she will be asked to recall related items. In other words, encoding was intentional for association and incidental in relation. Interestingly, a short sleep period benefits preferentially on intentionally encoded memory trace over incidentally ones (Drosopoulos et al., 2005). This limitation is inherent to the associative inference task, and has not, to our knowledge, yet been addressed in previous investigations. We therefore encourage future studies to modify the associative inference task to take this limitation into account (e.g. by making the association incidental). It would also be interesting to compare whether sleep modulation of relational performance differs according to the intentionality of learning.

One interesting and surprising result of this study is that the benefits of the rest period of associative performance did not depend on whether or not a nap took place during this period. The result did not also significantly differ for relational performance. Moreover, memory performance was not significantly influenced by the subjective time spent napping. One explanation could be that sleep had no additional effect on memory and did not alter the process of consolidation. Another explanation could be that the beneficial effect of sleep was masked by the short time window proposed. One theory of sleep-related memory improvement is that there is less interference arising from the world during sleep to disrupt memory (see Talamini et al., 2008). Protection from interference cannot satisfactorily account for the present study result as free and relational recall were not significantly improved. Therefore, it is reasonable to consider that rest has a beneficial effect on the associative performance on its own. This proposition is consistent with the research of Craig et al. (2015) who have shown that individuals who had a rest immediately after learning spatial association in a VR environment performed better in recalling certain specificities of these associations such as temporality. This benefit of awake rest was also demonstrated on associative performance itself (Craig et al., 2016). The environment used in the two mentioned studies was larger than the one used in the present research since it offered a complete segment of a realistic small town. The way in which a resting period allows the association of elements with a spatial component therefore appears to be robust. This result is also consistent with the proposition that wakeful rest can be considered as a specific state of consciousness that actively benefits the consolidation process. To our knowledge and as specified by the authors of the two studies mentioned above, the benefit of a rest period on associative performance is mainly studied with an interest in sleep. In contrary, the present study invites to consider the benefit of a rest period that possibly not contain a nap on the associative properties of memory.

Conclusion

We demonstrated that memory for associated items is enhanced by a rest period comparatively to a period of active wake. In perspective, we propose that future studies test this improvement with an even shorter duration and assess whether such a rest period could be useful in an academic learning context. The virtual environment proposed in this study has succeeded in highlighting the consolidation process that took place during a period of rest on associative properties of memory. Virtual reality offers an unparalleled opportunity to study memory consolidation for associations containing a spatial component because it places the individual in a simulation of a credible environment. As such, it allows both an experimental rigour in the presentation of objects comparable to other computerised tasks (e.g. randomisation, brightness control) while proposing a three-dimensional environment analogous, in terms of spatiality, to ones in which the individual evolves in his or her daily life. Virtual reality is already used in research by various disciplines, such as psychology (e.g., Sauzéon et al., 2012), neuroscience (e.g., Bohil et al., 2011), human-computer interaction (Coeugnet et al., 2018) or biology (e.g. Theart et al., 2017). This availability may indicate that VR has reached sufficient maturity to be integrated into a broader spectrum of scientific research projects, even if they are of moderate scale. The present study was conducted in the context of a larger project on the use of the virtual environment and user experience. Designing and administrating our environment and protocol were highly informative and led to several recommendations that we believe could be useful to other researchers. A first recommendation that may be obvious has emerged empirically and is intended for cognitive researchers; we believe that expertise in virtual environments and user experience should be sought before starting the development of studies that rely on VR. To contextualise this view, we need to indicate that this research is the result of spontaneous discussions that were encouraged by shared open space that enables interactions among researchers from different fields or theoretical backgrounds. Without these discussions, the protocol would not have taken into account some of the specificity of VR use. More specifically, these interdisciplinary exchanges led to the establishment of a series of constraints that guided the development of the protocol. For example, these constraints concerned: maximum duration of the environment, the addition of interaction with a plausible effect on the environment, the quality of the headset to be used in terms of framerate, the

Figure 1 :
1Screen capture of the Associative Spatialised Memory Room.

Figure 2 :
2the steps of the learning phases (identify the display stand, go to the display and open it by placing his or her hand on the button, observe the object, and go back to the black cross to state the object 's name out-lout). These steps were repeated 12 times for each learning (A-B and B-C). The order was randomised by the software. The individual in these pictures only serves as a representation of the participant and was not present in the environment during the learning process.

Figure 3 :
3during the associative recall the participant saw an object (depicted here using a square) on a display stand in the middle of the room and he/she could grab a laser pointer to indicate where he/she thought to have seen the object.

Figure 4 :
4during the relational recall the participant saw an object (depicted hereas a square) on a table inside a neutral environment. He or she had to indicate out-loud which object was in the same position during the learning phase.

Figure 5 :
5Course of the protocol for all participants

Figure 6 :
6Performance for the rest and the wake group for the free recall, the associative recall and the relational recall.
Twelve people participated in the pre-testing of the protocols. Six undergraduate students were trainees at the research centre. The others were all members of our psychology research center.

However, clear documentation to guide psychologists and research engineers in the development of their protocol with more care is, to our knowledge, still necessary. A review specifically addressing the use of VR when investigating episodic memory have been published since we elaborated this study. the addition of sensory multimodality, freedom of movement and the size and properties of the room, etc. SlaterThese constraints aimed to improve both interactive immersion and the coherence of sensory input. A massive amount of research on VR technologies has been conducted in the past 30 years. it could possibly complete and extend some of the recommendations we emitted presently (Smithof a flicker of light, the addition of sensory multimodality, freedom of movement and the size and properties of the room, etc. These constraints aimed to improve both interactive immersion and the coherence of sensory input. A massive amount of research on VR technologies has been conducted in the past 30 years (Slater, 2018). Researchers interested in using VR for research can rely on studies on presence (e.g. Slater, 1999), cyber sickness (e.g. Serge and Moss, 2015) and usability of virtual environments (e.g. Bach & Scapin, 2003). However, clear documentation to guide psychologists and research engineers in the development of their protocol with more care is, to our knowledge, still necessary. A review specifically addressing the use of VR when investigating episodic memory have been published since we elaborated this study, it could possibly complete and extend some of the recommendations we emitted presently (Smith, 2019).

We would like to thank the Picardy regional authority and the European Regional Development Fund. We would like to thank the Picardy regional authority and the European Regional Development Fund

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