Proust and involuntary retrieval.

Proust was undoubtedly a pioneer in exploring cognitive processes engaged in memory. The analysis of the episode of the madeleine, as well as the study of Proust's statements on the goals of his work, clearly reveal the visionary side of this author. Long before several concepts entered into mainstream scientific thought, Proust proposed, among other things, that recall was a reconstruction, that a sensory cue could provoke a memory recall, and that we should distinguish between voluntary and involuntary memory. Through numerous episodes of "involuntary reminiscence" scattered throughout his work, Proust illustrates a particular form of autobiographic memory recall: a recall that does not involve consciousness and whose starting point is an emotion provoked by a specific cue. This recall, which leads, according to Proust, to a more intense revival of the memory than voluntary recall, has only reached prominence in cognitive science more than 80 years later. Additionaly, Proust underlined the determinant role that emotion may have in this particular form of recall. On the other hand, studies on animals have shown that the presentation of a retrieval cue could induce emotional reactions followed by a facilitation of the memory retrieval associated with the cue. The existence of these data, which support Proust's proposals, should encourage the neuroscience community to further explore, in humans and animals, this form of cue elicited emotion that initiated involuntary recall of autobiographical memory.

Revisiting systems consolidation and the concept of consolidation.

For more than 50 years, knowledge of memory processes has been based on the consolidation hypothesis, which postulates that new memories require time to become stabilized. Two forms of the consolidation model exist. The Cellular Consolidation concept is based upon retrograde amnesia induced by amnesic treatments, the severity of which decreases as the learning to treatment increases over minutes or hours. In contrast, The Systems Consolidation model is based on post-training hippocampal lesions, which produce more severe retrograde amnesia when induced after days than after weeks. Except for the temporal parameters, Cellular and Systems Consolidation show many similarities. Here we propose that Systems consolidation, much as Cellular Consolidation (see Gisquet- Verrier and Riccio, 2018), can be explained in terms of a form of state-dependency. Accordingly, lesions of the hippocampus induce a change in the internal state of the animal, which disrupts retrieval processes. But the effect of contextual change is known to decrease with the length of the retention intervals, consistent with time-dependent retrograde amnesia. We provide evidence supporting this new view.

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD.

Recent evidence indicates that reactivated memories are malleable and can integrate new information upon their reactivation. We injected rats with oxytocin to investigate whether the delivery of a drug which dampens anxiety and fear before the reactivation of trauma memory decreases the emotional load of the original representation and durably alleviates PTSD-like symptoms. Rats exposed to the single prolonged stress (SPS) model of PTSD were classified 15 and 17 days later as either resilient or vulnerable to trauma on the basis of their anxiety and arousal scores. Following 2 other weeks, they received an intracerebral infusion of oxytocin (0.1 µg/1 µL) or saline 40 min before their trauma memory was reactivated by exposure to SPS reminders. PTSD-like symptoms and reactivity to PTSD-related cues were examined 3-14 days after oxytocin treatment. Results showed that vulnerable rats treated with saline exhibited a robust PTSD syndrome including increased anxiety and decreased arousal, as well as intense fear reactions to SPS sensory and contextual cues. Exposure to a combination of those cues resulted in c-fos hypo-activation and dendritic arbor retraction in prefrontal cortex and amygdala neurons, relative to resilient rats. Remarkably, 83% of vulnerable rats subjected to oxytocin-based emotional remodeling exhibited a resilient phenotype, and SPS-induced morphological alterations in prelimbic cortex and basolateral amygdala were eliminated. Our findings emphasize the translational potential of the present oxytocin-based emotional remodeling protocol which, when administered even long after the trauma, produces deep re-processing of traumatic memories and durable attenuation of the PTSD symptomatology.

Post Traumatic Stress Disorder and Substance Use Disorder as Two Pathologies Affecting Memory Reactivation: Implications for New Therapeutic Approaches.

In the present review, we provide evidence indicating that although post traumatic stress disorder (PTSD) and substance use disorder (SUD) are two distinct pathologies with very different impacts on people affected by these chronic illnesses, they share numerous common characteristics, present high rates of co-morbidity, and may result from common physiological dysfunctions. We propose that these pathologies result from hyper reactivity to reminders, and thus should be considered as two disorders of memory, treated as such. We review the different possibilities to intervene on pathological memories such as extinction therapy and reconsolidation blockade. We also introduce new therapeutic avenues directly indicate by our recent proposal to replace the consolidation/reconsolidation hypothesis by the integration concept. State dependency and emotional remodeling are two innovative treatments that have already provided encouraging results. In summary, this review shows that the discovery of reactivation-dependent memory malleability has open new therapeutic avenues based on the reprocessing of pathological memories, which constitute promising approaches to treat PTSD and SUD.

Behavioral and Noradrenergic Sensitizations in Vulnerable Traumatized Rats Suggest Common Bases with Substance Use Disorders.

The aim of the present study was to strengthen our hypothesis of a common physiological basis for post-traumatic stress disorder (PTSD) and substance use disorders. This paper investigates the possibility that rats exposed to a PTSD model exhibit noradrenergic and behavioral sensitization, as observed following repeated drugs of abuse injections. First, rats received a single prolonged stress (SPS), combining three consecutive stressors. They were then tested, 2 weeks after the trauma for PTSD-like symptoms to discriminate between vulnerable and resilient rats. When microdialysis was performed in the prelimbic cortex (Experiment 1), larger increases of noradrenaline (NA) release in response to amphetamine were observed in vulnerable rats when compared to control and resilient animals. Experiment 2 showed that trauma-vulnerable rats exhibited increases in locomotor activity relative to controls, in response to an exposure to trauma-associated cues. These data demonstrate that a single trauma exposure induces in vulnerable animals both, a noradrenergic sensitization evidenced within the prelimbic cortex and behavioral sensitization obtained after a physiologic activation of the noradrenergic system. However, Experiment 3 showed that when NA system was activated by amphetamine (1 mg/kg), a decrease in behavioral sensitization was obtained in vulnerable rats. We proposed that this decreased locomotor activity results from an additional stress-induced increased reactivity of mesocortical dopaminergic neurons, known to counteract the consequences of cortical noradrenergic release in rats. These results support our hypothesis that noradrenergic sensitization represents a common physiological basis, involved both in PTSD and drug addiction and suggest new common therapeutic approaches for these pathologies.

Memory integration: An alternative to the consolidation/reconsolidation hypothesis.

The original concept of consolidation considers that memory requires time to be fixed. Since 2000, a comparable protein-dependent re-stabilization phase, called reconsolidation, has been assumed to take place after memory retrieval. This consolidation/reconsolidation hypothesis, has dominated the literature for more than 50 years, despite compelling evidence that is inconsistent with it. In this review, we present an historical overview and explain how, despite serious criticisms, this hypothesis has persisted for decades and become accepted as a dogma. Based on both older and more recent evidence, we next propose the concept of memory integration which involves the linkage or embedding of new material into an already existing representation. We believe integration provides a viable explanation for retrograde amnesia in place of the consolidation/reconsolidation hypothesis. Integration can further be the basis for several major cases of memory alteration such as time dependent memory enhancement, interference, counter-conditioning, updating and other instances of memory malleability. In a final section we consider the implications this new concept may have for memory processes and its translational applications.

Memory Integration as a Challenge to the Consolidation/Reconsolidation Hypothesis: Similarities, Differences and Perspectives.

We recently proposed that retrograde amnesia does not result from a disruption of the consolidation/reconsolidation processes but rather to the integration of the internal state induced by the amnesic treatment within the initial memory. Accordingly, the performance disruption induced by an amnesic agent does not result from a disruption of the memory fixation process, but from a difference in the internal state present during the learning phase (or reactivation) and at the later retention test: a case of state-dependency. In the present article, we will review similarities and differences these two competing views may have on memory processing. We will also consider the consequences the integration concept may have on the way memory is built, maintained and retrieved, as well as future research perspectives that such a new view may generate.

[Common physiological basis for post-traumatic stress disorder and dependence to drugs of abuse: Implications for new therapeutic approaches]. / Bases physiologiques communes pour les troubles de stress post-traumatique et la dépendance aux drogues d'abus : conséquences pour de nouvelles approches thérapeutiques.

Post-traumatic stress disorder (PTSD) and addiction to drugs of abuse are two common diseases, showing high comorbidity rates. This review presents a number of evidence showing similarities between these two pathologies, especially the hyper-responsiveness to environmental cues inducing a reactivation of the target memory leading either to re-experiencing (PTSD), or drug craving. Accordingly, PTSD and addiction to drug of abuse might by considered as memory pathologies, underlined by the same physiological process. We propose that these two pathologies rely on an uncoupling of the monoaminergic systems. According to this hypothesis, exposure to extreme conditions, either negative (trauma) or positive (drugs) induced a loss of the reciprocal control that one system usually exerts on the other monoaminergic system, resulting to an uncoupling between the noradrenergic and the serotonergic systems. Results obtained in our laboratory, using animal models of these pathologies, demonstrate that after a trauma, such as after repeated drug injections, rats developed both a behavioral sensitization (increases of the locomotion in response to a stimulation of the monoaminergic systems) and a pharmacological sensitization (increases of noradrenergic release within the prefrontal cortex). These results support our hypothesis and led us to propose new and innovative therapeutic approaches consisting either to induce a re-coupling of the monoaminergic systems, or to modify the pathological memories by using an emotional memory remodeling. Extremely encouraging results have already been obtained in rats and in humans, opening new and promising therapeutic avenues.

Effects of multiple brief exposures to trauma-associated cues on traumatized resilient and vulnerable rats.

Intrusive re-experiencing of a trauma is a core symptom in post-traumatic stress disorder (PTSD), and is often triggered by contextual cues associated with the event. It is not yet established if intrusive re-experiencing is the consequence of PTSD, or if it could contribute to the development of PTSD following a traumatic event. The present study (1) examined the impact of repeated brief re-exposures to trauma reminders on the strength of PTSD-like symptoms, as well as on their time-development and (2) investigated the reactivity over time to these cues in trauma resilient and vulnerable rats, defined on the basis of the PTSD-like symptoms they demonstrated. Rats were exposed to a Single Prolonged Stress, combining three different stresses (2-h restraint, 20-min forced swim and CO2 unconsciousness) delivered together with tone and odor cues and preceded by an inhibitory avoidance conditioning or a control procedure. During the following two weeks, reminded rats were briefly re-exposed to trauma-associated cues either 4 or 8 times. The results indicated that 4 re-exposures to the same cue strengthened PTSD-like symptoms (anxiety, arousal, fear to trauma-cue). However 8 re-exposures to similar or different trauma-cues did not alter PTSD-like symptoms and led to a rapid extinction of the fear reactivity to these cues. The present results further indicated that shortly after trauma, both resilient and vulnerable rats strongly reacted to trauma-associated cues, while only vulnerable rats reacted long after the trauma, suggesting a slower loss of fear responses to trauma cues in these rats. We concluded that re-experiencing may participate in, but cannot be solely responsible for, the development of long-term PTSD effects.

Sensitivity to trauma-associated cues is restricted to vulnerable traumatized rats and reinstated after extinction by yohimbine.

While post-traumatic stress disorder (PTSD) symptom is mainly characterized by re-experiencing the traumatic event, the reactivity to trauma-associated cues in resilient and vulnerable subjects has not been extensively studied. Using an animal model of PTSD induced by a single prolonged stress (SPS), the responses of traumatized Vulnerable and Resilient rats to PTSD-like symptom tests and to trauma-associated cues were investigated. In addition, the implication of the noradrenergic system in "re-experiencing" was explored. Rats received either a SPS, combining a 2h restraint stress, a 20min forced-swim followed by a 15min rest, and a loss of consciousness produced by inhaling CO2 emissions, delivered in the presence of particular cues (tone and odor), or a control procedure. PTSD-like symptoms and reactivity to various trauma-associated cues (specific, contextual, or predictive) were tested from D15 to D60 after the SPS. Rats were then divided into Resilient and Vulnerable on the basis of three main symptom tests, including the elevated plus maze, the light-dark and the acoustic startle response tests. Although Resilient rats behaved like Controls rats, Vulnerable rats developed long-term PTSD-like symptoms on the main symptoms tests (anxiety and alteration of arousal), as well as other PTSD-like outcomes (such as anhedonia and avoidance to trauma-associated cues). These Vulnerable rats were also the only ones to demonstrate strong reactivity to trauma-associated cues. In addition, the alpha-2 adrenergic receptor antagonist, Yohimbine (i.p., 1.5mg/kg/ml), was able to reinstate fear responses to an extinguished trauma-associated odor. Our results established clear relationships between Vulnerability to trauma and reactivity to trauma-associated cues and further suggest an involvement of the noradrenergic system.

Repeated amphetamine injections alter behavior and induce a delayed behavioral sensitization modulated by reactivity to novelty: Similarities and differences with trauma consequences.

Supporting our hypothesis of common biological bases for post-traumatic stress disorder (PTSD) and addiction, we recently reported that rats exposed to a single prolonged stress (SPS), a PTSD model, develop a delayed behavioral sensitization of the noradrenergic system, similar to that observed in mice after four repeated drug administrations. However, sensitization after trauma was modulated by reactivity to novelty, and this aspect that had not been explored in the addiction model. The first aim of the paper was thus to investigate the influence of reactivity to novelty on delayed behavioral sensitization in rats after four repeated amphetamine injections. Injections were either distributed over 4 days, as conducted in mouse models of addiction, or massed during a single session, reproducing SPS conditions. The second aim was to investigate whether repeated amphetamine injections have similar behavioral consequences to those induced by PTSD. Our results showed that massed amphetamine injections induced more anxiety than distributed injections, and led to avoidance of drug-associated cues avoidance, while distributed injections somewhat reduced the startle response, such as is seen in SPS. In addition, massed amphetamine injections induced a delayed behavioral sensitization clearly affected by the reactivity to novelty, reproducing results observed following exposure to traumatic events. Finally, all rats receiving repeated amphetamine injections exhibited a behavioral sensitization in response to exposure to drug-associated cues. Taken together, these data strengthen the position that drug addiction and PTSD share some common mechanisms that we tried to clarify in this paper.

PIXSIC: A Wireless Intracerebral Radiosensitive Probe in Freely Moving Rats.

The aim of this study was to demonstrate the potential of a wireless pixelated ß+-sensitive intracerebral probe (PIXSIC) for in vivo positron emission tomographic (PET) radiopharmacology in awake and freely moving rodents. The binding of [(11)C]raclopride to D2 dopamine receptors was measured in anesthetized and awake rats following injection of the radiotracer. Competitive binding was assessed with a cold raclopride injection 20 minutes later. The device can accurately monitor binding of PET ligands in freely moving rodents with a high spatiotemporal resolution. Reproducible time-activity curves were obtained for pixels throughout the striatum and cerebellum. A significantly lower [(11)C]raclopride tracer-specific binding was observed in awake animals. These first results pave the way for PET tracer pharmacokinetics measurements in freely moving rodents.

Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?

Active (new and reactivated) memories are considered to be labile and sensitive to treatments disrupting the time-dependent consolidation/reconsolidation processes required for their stabilization. Active memories also allow the integration of new information for updating memories. Here, we investigate the possibility that, when active, the internal state provided by amnesic treatments is represented and integrated within the initial memory and that amnesia results from the absence of this state at testing. We showed in rats that the amnesia resulting from systemic, intracerebroventricular and intrahippocampal injections of the protein synthesis inhibitor cycloheximide, administered after inhibitory avoidance training or reactivation, can be reversed by a reminder, including re-administration of the same drug. Similar results were obtained with lithium chloride (LiCl), which does not affect protein synthesis, when delivered systemically after training or reactivation. However, LiCl can induce memory given that a conditioned taste aversion was obtained for a novel taste, presented just before conditioning or reactivation. These results indicate that memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation. The findings more likely support the integration hypothesis: posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval. This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory. SIGNIFICANCE STATEMENT: This study provides evidence challenging the traditional consolidation/reconsolidation hypotheses that have dominated the literature over the past 50 years. Based on amnesia studies, that hypothesis states that active (i.e., new and reactivated) memories are similarly labile and (re)established in a time-dependent manner within the brain through processes that require de novo protein synthesis. Our data show that new/reactivated memories can be formed without protein synthesis and that amnesia can be induced by drugs that do not affect protein synthesis. We propose that amnesia results from memory integration of the internal state produced by the drug that is subsequently necessary for retrieval of the memory. This interpretation gives a dynamic view of memory, rapidly stored and easily updated when active.

Spatial radial maze procedures and setups to dissociate local and distal relational spatial frameworks in humans.

BACKGROUND: Radial maze tasks have been used to assess optimal foraging and spatial abilities in rodents. The spatial performance was based on a capacity to rely on a configuration of local and distant cues. We adapted maze procedures assessing the relative weight of local cues and distant landmarks for arm choice in humans. NEW METHOD: The procedure allowed testing memory of places in four experimental setups: a fingertip texture-groove maze, a tactile screen maze, a virtual radial maze and a walking size maze. During training, the four reinforced positions remained fixed relative to local and distal cues. During subsequent conflict trials, these frameworks were made conflictive in the prediction of reward locations. RESULTS: Three experiments showed that the relative weight of local and distal relational cues is affected by different factors such as cues' nature, visual access to the environment, real vs. virtual environment, and gender. A fourth experiment illustrated how a walking maze can be used with people suffering intellectual disability. COMPARISON WITH EXISTING METHODS: In our procedure, long-term (reference) and short-term (working) memory can be assessed. It is the first radial task adapted to human that enables dissociating local and distal cues, to provides an indication as to their relative salience. Our mazes are moveable and easily used in limited spaces. Tasks are performed with realistic and spontaneous though controlled exploratory movements. CONCLUSION: Our tasks enabled highlighting the use of different strategies. In a clinical perspective, considering the use of compensatory strategies should orient towards adapted behavioural rehabilitation.

Only susceptible rats exposed to a model of PTSD exhibit reactivity to trauma-related cues and other symptoms: an effect abolished by a single amphetamine injection.

The present study had two main goals. First, to investigate whether an animal model of post traumatic stress disorder (PTSD), single prolonged stress (SPS) leads to one of the main PTSD symptom: avoidance of trauma-related stimuli. Second, to investigate whether a single amphetamine injection delivered 30 days after SPS can reduce these symptoms. Olfactory and auditory cues were added to the SPS context and reactivity to these cues were tested more than one month later using an odor discrimination test, and freezing to the trauma-related tone. Other PTSD symptoms, such as anxiety (elevated plus maze) and hyperarousal (acoustic startle response), were also investigated in these rats. Some behavioural reactivity to the environmental cues was observed in rats exposed to SPS. However, a subgroup of these rats showed an exaggerated disruption in performance in 3 to 4 of the behavioral tests relative to controls, suggesting that two classes of rats, those that are susceptible and those that are resilient to SPS, can be dissociated. When rats were treated with amphetamine (1mg/kg) injected in the SPS context 30 days after SPS, traumatized rats no longer differed from their corresponding controls and all were identified as resilient. The present data demonstrated that rats exposed to SPS can be either susceptible or resilient and a single amphetamine injection can abolish the associated symptoms. We propose that combining memory reactivation, with an amphetamine-induced positive mood, can modify the emotional valence of the initial memory, inducing long-lasting remodeling of the traumatic memory, thereby opening a novel therapeutic avenue.

Traumatic stress in rats induces noradrenergic-dependent long-term behavioral sensitization: role of individual differences and similarities with dependence on drugs of abuse.

RATIONALE: The aim of this paper is to provide evidence for the hypothesis that posttraumatic stress disorder (PTSD) and drug addiction rely on common processes. OBJECTIVE: Our objective is to show that a noradrenergic-dependent behavioral sensitization occurs after the development of PTSD, in a way similar to that recently demonstrated after repeated drug injections. METHODS: Rats classified into high and low responders to novelty (HR/LR) were subjected to a single prolonged stress (SPS). Cross-sensitization was evaluated after d-amphetamine injection (1.0 mg/kg) in a locomotor activity test given either 4, 15, or 90 days later. To determine the involvement of the noradrenergic system, rats were injected with the α2-receptor agonist, clonidine (20 µg/kg), during the SPS. Subsequently, their auditory startle response (ASR) and cross-sensitization were assessed. RESULTS: SPS affected both the hypothalamic-pituitary-adrenal axis and the ASR, replicating some PTSD-like symptoms. Behavioral sensitization was found after 15, 21, and 90 days after the SPS in LR rats, and a behavioral desensitization in HR rats after 15 days. Clonidine delivered during the SPS prevented the behavioral sensitization in LR rats, as well as the effects on ASR in HR and LR rats. CONCLUSIONS: Exposure to SPS is shown to affect behavior and induce a behavioral sensitization to d-amphetamine that is modulated by individual differences. Both of these effects depend on the noradrenergic system. Altogether, the present results (1) replicate findings obtained after repeated drug exposure and (2) strengthen our hypothesis of a common physiological basis between PTSD and drug addiction.