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

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

PIXSIC: A Wireless Intracerebral Radiosensitive Probe in Freely Moving Rats

International audienceThe aim of this study was to demonstrate the potential of a wireless pixelated β+-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 D 2 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

Comparing integration and contextual binding accounts of memory impairment

International audienceIn their recent Opinion (A contextual binding theory of episodic memory: systems consolidation reconsidered. Nat. Rev. Neurosci. 20, 364–375 (2019)), Yonelinas et al. reconsidered the standard systems consolidation theory (SSCT) and proposed the contextual binding theory (CBT). For these authors, the long-term development of memory and forgetting can be explained by the way information has been bound during memory formation. Information will be forgotten because different material that occurs in the same context interferes with the item to be learned. The authors propose that CBT can explain better than the SSCT several forgetting effects, including interference effects and retrograde amnesia after post-training hippocampal lesions.We were pleased to see that this CBT view has much in common with our own ‘integration concept’ (IC), which we introduced to challenge the consolidation–reconsolidation hypothesis. According to the IC, memories, when in an active state (after training or reactivation), become malleable and integrate new information that is present. Depending on the information available at that time, memories can be updated, strengthened (by coherent information), disrupted (by incoherent information resulting from, for example, amnesic treatments or interference) or greatly altered (false memory). We have described evidence showing that performance disruption due to post-training amnesic treatments mainly results from impairments in retrieval that are induced by contextual differences between training and testing.There are clear convergences between CBT and the IC model. Both accounts challenge the long-held consolidation hypotheses and emphasize a prominent role of environmental context (internal and external) as a major determinant of forgetting. Both accounts note that contextual information presented just before or just after the study event have similar effects on memory, a concept consistent with recent findings.However, some essential differences should also be noted. Although both IC and CBT claim to explain temporally graded retrograde amnesia, they do not address the same consolidation processes. IC proposes to explain retrograde amnesia resulting from amnesic treatments delivered during the first minutes following training and thus affecting presumed consolidation–reconsolidation processes. By contrast, CBT suggests an explanation for retrograde amnesia resulting from hippocampal lesions administered days to weeks after training, therefore concerning standard systems consolidation.Another principal difference between the two frameworks concerns the origin of memory impairment. For CBT, the main source of forgetting is interference between memories that share similar context or content during memory formation. The IC account proposes that forgetting results from a contextual mismatch between acquisition and testing, inducing retrieval difficulties10. In agreement with the IC, active memories are malleable and integrate any contextual information present. Accordingly, interference is only one source of disruption, among others. As a consequence, the IC model can account for various performance modulations, such as anterograde and retrograde amnesia5,6, interference, false memories, as well as counterconditioning and promnesic effects.Interestingly, the recent literature seems to converge towards the same aim: revisiting serious shortcomings of older theories of memory impairment. By doing that, CBT and IC both serve to stimulate new conceptions of memory

Prelimbic cortex specific lesions disrupt delayed-variable response tasks in the rat.

International audienceThe role of the prelimbic cortex (PL) in rats was investigated with excitotoxic lesions. PL lesions altered the alternation scores in spontaneous and reinforced spatial delayed-alternation tasks. PL lesions induced a delay in conditioning under a temporal go/no-go alternation schedule but not under a continuous food-reinforcement schedule in a runway. PL lesions had no effect on the acquisition of a standard radial-arm-maze task nor on a fixed-goal location task but disrupted the acquisition of a variable-goal location task in a radial-arm maze. The present results indicate that PL lesions replicated most of the behavioral deficits obtained with larger prefrontal lesions. PL lesions disrupted the acquisition of delayed-variable response tasks while leaving unaffected fixed-response tasks. These results are discussed in relation with a working-memory, a response-selection, and an attentional hypothesis

Rôle fonctionnel des aires prélimbique et infralimbique du cortex préfrontal médian (une implication dans la résolution de conflits ?)

Les aires prélimbique (PL) et infralimbique (IL) du cortex préfrontal médian (CPFm) du rat sont impliquées dans de nombreux processus cognitifs. Le but de ma thèse est de déterminer s il existe une fonction supra-modalitaire pouvant rendre compte de l ensemble des données de la littérature. Pour cela, l effet de dysfonctionnements des cortex PL ou/et IL (lésion, inactivation, blocage des récepteurs dopaminergique D1) a été étudié dans une nouvelle épreuve automatisée de changements de stratégie et dans l extinction d une peur conditionnée. Les lésions du CPFm perturbent changements de règles et renversements. L analyse fine du comportement indique que les lésions du CPFm perturbent l adoption d une stratégie en conflit avec un apprentissage antérieur, l IL étant impliqué dans le choix initial de cette stratégie et le PL dans son maintien. L injection locale d un antagoniste D1 et l inactivation du PL conduisent à des résultats différents semblant résulter de dérégulations locales et à distance. Les lésions PL/IL retardent l extinction d une peur conditionnée lorsque le stimulus conditionnel est ambigu, c'est-à-dire lorsque l extinction a lieu dans un contexte différent de celui du conditionnement et lorsque l association initiale est réactivée par restauration de la peur. Nos données indiquent que le CPFm joue un rôle dans les processus d interférence proactive. Sur la base de ce travail et de l examen de la littérature, nous proposons que les aires PL/IL soient impliquées dans la résolution de conflits, l incidence sur d autres processus, comme la flexibilité comportementale, pouvant n être que la conséquence de ce déficit.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Etude de l'évolution et du rappel des représentations mnésiques chez le rat

L'étude de l'évolution des stratégies comportementales au cours d'un apprentissage a mis en évidence que, dans une épreuve de labyrinthe en T, les rats choisissent indifféremment une stratégie spatiale ou égocentrée en début d'apprentissage, puis adoptent une stratégie égocentrée. Des lésions, du CPFm ventral conduisent au maintien d'un choix équilibré des stratégies. Des lésions du striatum dorsal favorisent l'utilisation précoce d'une stratégie égocentrée. Notre étude a montré que l'évolution des stratégies dépend de l'épreuve, de structures cérébrales comme le cortex PL-IL, mais pas de l'intégrité des boucles cortico-striatales. L'étude du mécanisme d'action des indices de rappel a montré que, dans une épreuve d'évitement en discrimination lumineuse, la présentation de lac lumière à 1 jour ou du contexte expérimental à 21 jours améliore les performances de rétention et s'accompagne d'une activation de l'axe corticotrope, dont le blocage par un antagoniste CRF1 bloque l'effet facilitateur de la lumière. La naloxone (antagoniste opiacé), qui bloque les effets comportementaux des indices de rappel, diminue spécifiquement les taux d'ACTH après exposition à un indice de rappel. Ces données indiquent un lien de causalité notamment entre le CRF et les indices de rappel, qui pourrait s'exercer au niveau de l'amygdale. L'étude des bases structurales a révélé que des lésions du CPFm annihilent tout effet des indices de rappel. Au sein du SD, seule la partie latérale est impliquée dans les processus de rappel. La présentation d'un indice de rappel lumineux diminue les taux de PhosphoERK dans le CPF et l'amygdale, indiquant que une implication des voies des MAPK. Ces données permettent d'établir un schéma explicatif possible des mécanismes d'action mis enjeu lors de la présentation d'un indice de rappel. Il semble, comme chez l'homme, que deux formes de rappel puissent être mises en évidence par la nature des processus de recherche et les structures cérébrales impliqués.Rats learning a T-maze task initially use a spatial or egocentric strategy but progressively change over time to predominantly an egocentric approach. Lesions to the ventral part of the medial prefrontal cortex (mPFC) block this change of strategy, such that both strategies are equally chosen even after overtraining, whereas, lesions to the dorsal striatum lead to an early choice of the egocentric strategy. Our study shows that the change of strategy depends on the task, and on brain structures such as the PL-IL cortex, but not on cortico-striatal circuits. Study of mechanisms underlying the effects of retrieval cues indicate that, in a brightness discrimination avoidance task, exposure to the light discriminative stimulus or to the experimental context enhances retention performance when the test is delivered 1 and 21 days, respectively, after training. This behavioural effect is accompanied by an activation of the stress axis, and interruption by a CRF1 antagonist blocks the facilitative effect of light. Naloxone (an opoid antagonist) disrupts the behavioural effect of retrieval cues and decreases significantly the ACTH levels after exposure to the retrieval cue. These data indicate a causal link between CRF and retrieval cues that could exist in the amygdala. The mPFC was implicated~ whereby lesions of the area block the facilitative effect of the retrieval cues. A functional dissociation is observed in the dorsal striatum: only the lateral part being involved in retrieval processes. Exposure to the light decreases the PhosphoERK levels in the PFC and in the amygdala, indicating an involvement of the MAPK cascades. These data suggest explicit circuits underlying the processes involved following exposure to retrieval cues. It appears that, as in humans, two forms of retrieval can be observed, dependent upon the test used and brain structures involved.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

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.

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Decision making guided by emotion

International audienceA computational architecture is presented, in which “swift and fuzzy” emotional channels guide a “slow and precise” decision-making channel. Reported neurobiological studies first provide hints on the representation of both emotional and cognitive dimensions across brain structures, mediated by the neuromodulation system. The related model is based on Guided Propagation Networks, the inner flows of which can be guided through modulation. A key-channel of this model grows from a few emotional cues, and is aimed at anticipating the consequences of on-going possible actions. Current experimental results of a computer simulation show the integrated contribution of several emotional influences, as well as issues of accidental all-out emotions