Mécanismes cellulaires, moléculaires et physiologique à la base du traitement des interférences proactives chez le rat

Contrary to popular opinion forgetting can be useful: it will allow the filtering of non-essential information. The work of this thesis is to determine the biological basis of such adaptive forgetting, especially in the context of working memory (WM). We have adopted a comparative approach through the training of rats in a three behavioral tasks in a radial maze designed to test three distinct cognitive processes: the long-term memory, WM and treatment of proactive interference (PI). We have shown that information supposed to be stored in WM could last longer than necessary and interfere later with the storage of new information. Forgetting the first tests is therefore necessary to avoid PI. To understand the biological basis for this forgetting, we used three methodological approaches. We performed an immunohistochemical study aiming to understand what the brain region underlies the PI processing. This study showed that this processing requires inactivation of the dentate gyrus of the hippocampus. We then performed Western blot analysis in order to identify the molecular processes underlying this inhibition. This study shows that, in the hippocampus, different synaptic plasticity processes may occur during treatment of PI. The third approach is to understand when this processing occurs. This study shows a slow sleep role in the treatment of PIContrairement à l'opinion populaire l'oubli pourrait être utile: il permettrai le filtrage des informations non-essentielles. Le travail de cette thèse vise à déterminer les bases biologiques de cet oubli adaptatif, en particulier dans le contexte de la mémoire de travail (MT). Nous avons adopté une approche comparative grâce à l'entrainement de rats dans un trois taches comportementales dans un labyrinthe radial visant à tester trois processus cognitifs distincts: la mémoire à long terme, la MT et le traitement des interférences proactive (IP). Nous avons montré que l'information supposée être stockée en MT pouvait perdurer plus longtemps que nécessaire et interférer, plus tard, avec le stockage de nouvelles informations. L'oubli des premiers essais est donc nécessaire pour éviter les IP. Pour comprendre les bases biologiques de cet oubli, nous avons utilisé trois approches. Nous avons effectué une étude immunohistochimique visant à comprendre dans quelle région du cerveau le traitement des IP se produit. Cette étude a montré que ce traitement requiert l'inactivation du gyrus denté de l'hippocampe. Nous avons ensuite effectué une analyse en western-blot pour identifier les processus moléculaires à la base de cette inhibition. Cette étude montre que, dans l'hippocampe, différents processus de plasticité synaptique pourraient se produire pendant le traitement des IP. La troisième approche, vise à comprendre à quel moment ce traitement se produit. Cette étude montre un rôle du sommeil lent dans le traitement des IP. Ces travaux nous aident donc à identifier les mécanismes responsables de l'oubli utile d'informations et donc à mieux comprendre comment le cerveau gère les I

Working and Reference Memory Tasks Trigger Opposed Long-Term Synaptic Changes in the Rat Dentate Gyrus

International audienceLong-term storage of information into memory is supposed to rely on long-term synaptic plasticity processes. The detection of such synaptic changes after training in long-term/reference memory (RM) tasks has yet been scarce, variable and only studied on a short time scale. Short-term or working memory (WM) is largely known to depend on persistent neuronal activity or short-term plasticity. However, processing information into WM could also involve long-term synaptic changes that could be responsible for the erasure/forgetting of items previously stored in WM and acting as proactive interference. In order to study long-term synaptic changes associated with RM or WM, we trained chronically implanted rats in 3 different radial maze tasks: a classical RM task and 2 WM tasks involving different levels of proactive interference. Synaptic responses in the dentate gyrus were recorded during 2 × 24 h in freely moving rats after training. We found that consolidation of long-term information leads first to a delayed synaptic potentiation, occurring 9 h after RM training that is replaced by a synaptic depression once the RM rule is fully acquired. In contrast, optimal information processing into WM triggers a synaptic depression immediately after training and lasting 3 h that could act as a mechanism for interference erasure/forgetting

Working and Reference Memory tasks trigger opposed long-term synaptic changes in the rat dentate gyrus

International audienceAbstract Long-term storage of information into memory is supposed to rely on long-term synaptic plasticity processes. The detection of such synaptic changes after training in long-term/reference memory (RM) tasks has yet been scarce, variable and only studied on a short time scale. Short-term or working memory (WM) is largely known to depend on persistent neuronal activity or short-term plasticity. However, processing information into WM could also involve long-term synaptic changes that could be responsible for the erasure/forgetting of items previously stored in WM and acting as proactive interference. In order to study long-term synaptic changes associated with RM or WM, we trained chronically implanted rats in 3 different radial maze tasks: a classical RM task and 2 WM tasks involving different levels of proactive interference. Synaptic responses in the dentate gyrus were recorded during 2 × 24 h in freely moving rats after training. We found that consolidation of long-term information leads first to a delayed synaptic potentiation, occurring 9 h after RM training that is replaced by a synaptic depression once the RM rule is fully acquired. In contrast, optimal information processing into WM triggers a synaptic depression immediately after training and lasting 3 h that could act as a mechanism for interference erasure/forgetting

Working and Reference Memory Tasks Trigger Opposed Long-Term Synaptic Changes in the Rat Dentate Gyrus

International audienc

Long-term effects of interference on short-term memory performance in the rat

<div><p>A distinction has always been made between long-term and short-term memory (also now called working memory, WM). The obvious difference between these two kinds of memory concerns the duration of information storage: information is supposedly transiently stored in WM while it is considered durably consolidated into long-term memory. It is well acknowledged that the content of WM is erased and reset after a short time, to prevent irrelevant information from proactively interfering with newly stored information. In the present study, we used typical WM radial maze tasks to question the brief lifespan of spatial WM content in rodents. Groups of rats were submitted to one of two different WM tasks in a radial maze: a WM task involving the repetitive presentation of a same pair of arms expected to induce a high level of proactive interference (PI) (HIWM task), or a task using a different pair in each trial expected to induce a low level of PI (LIWM task). Performance was effectively lower in the HIWM group than in LIWM in the final trial of each training session, indicative of a “within-session/short-term” PI effect. However, we also observed a different “between-session/long-term” PI effect between the two groups: while performance of LIWM trained rats remained stable over days, the performance of HIWM rats dropped after 10 days of training, and this impairment was visible from the very first trial of the day, hence not attributable to within-session PI. We also showed that a 24 hour-gap across training sessions known to allow consolidation processes to unfold, was a necessary and sufficient condition for the long-term PI effect to occur. These findings suggest that in the HIWM task, WM content was not entirely reset between training sessions and that, in specific conditions, WM content can outlast its purpose by being stored more permanently, generating a long-term deleterious effect of PI. The alternative explanation is that WM content could be transferred and stored more permanently in an intermediary form or memory between WM and long-term memory.</p></div

Behavioral protocols used in Experiments 1 to 3.

<p>(A) Drawing code used to represent the radial maze. (B) Classic LIWM and HIWM training (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0173834#sec002" target="_blank">Materials and methods</a>) performed in Experiment 1, illustrated with one session (four trials). The pair of arms used for each trial is different for the LIWM training while it is identical for HIWM training. Training was spaced, meaning that two sessions were separated by 24h with a total of 10 sessions. The sequence of arms presentation shown in (B) is only informative and does not represent the sequence used each day. This sequence is different every day and pseudo-randomly determined by the experimenter. (C) In Experiment 2, the two tasks used were the same as in A), except that training was massed (mLIWM and mHIWM): each session was separated by 10 min, with 10 sessions on day 1 and 10 other sessions on day 2. (D) In Experiment 3, we used a spaced training as in A), but the arms used during the choice phase were no longer adjacent but formed a 90° angle (LIWM90 and HIWM90), as illustrated in the example.</p

Massed training prevents performance drop in the HIWM group but long-term proactive interference appears after a 24 hour-interruption that allows consolidation of the content of WM into a more durable form of memory.

<p>Percentage of correct choices across blocks of two sessions with a massed training of 10 sessions by day during two days. ANOVA revealed a significant Group effect only on day 2 (*** p < 0.001) due to lower performance in the HIWM group. A <i>split-by</i> Group analysis of performance on day 2 showed a significant improvement in HIWM trained animals leading to similar level of performance between the two groups on final block 10.</p

Performance drop in the final sessions of HIWM training reveals accumulation of PI across days, and hence long-lasting WM.

<p>(A) Evolution of the percentage of correct choices across blocks of two sessions, for rats trained in the LIWM or the HIWM task. ANOVA revealed a significant Group effect (*** p < 0.001), due to the drop of performance in the HIWM group across days revealed by the <i>split-by</i> Group analysis. (B) Percentage of correct choices made by trial for the first and the last 5 days of training, for the two groups. For Days 1 to 5 ANOVA revealed no Group effect but a significant Trial effect with a drop of performance on trial 4 for the HIWM group (Sidak's <i>post-hoc</i> test, * p < 0.05), indicative of short-term PI. On the contrary for days 6 to 10 there was a significant Group effect, due to lower performance in the HIWM group from the very first trial (Sidak's <i>post-hoc</i> test, ** p < 0.01). This reduction of performance in the HIWM task could not be attributable to short-term PI, but to accumulation of PI across days indicating that WM was not entirely reset at the end of each training and could partly last at least 24h.</p

Reducing the need for pattern separation prevents performance drop in the HIWM group.

<p>Percentage of correct choices across blocks of two sessions with a spaced training in the two tasks during which the angle between two choice arms was 90° to reduce the need for pattern separation relative to the same tasks with 45° spaced-arms as used in experiment 1. ANOVA revealed no Group effect (NS: non-significant).</p