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

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.

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

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.

Differential changes in hippocampal CaMKII and GluA1 activity after memory training involving different levels of adaptive forgetting.

Phosphorylation of CaMKII and AMPA receptor GluA1 subunit has been shown to play a major role in hippocampal-dependent long-term/reference memory (RM) and in the expression of long-term synaptic potentiation (LTP). In contrast, it has been proposed that dephosphorylation of these proteins could be involved in the opposite phenomenon of hippocampal long-term synaptic depression (LTD) and in adaptive forgetting. Adaptive forgetting allows interfering old memories to be forgotten to give new ones the opportunity to be stored in memory, and in particular in short-term/working memory (WM) that was shown to be very sensitive to proactive interference. To determine the role of CaMKII and GluA1 in adaptive forgetting, we adopted a comparative approach to assess the relative quantity and phosphorylation state of these proteins in the brain of rats trained in one of three radial maze paradigms: a RM task, a WM task involving a high level of adaptive forgetting, or a WM involving a low level of adaptive forgetting. Surprisingly, Western blot analyses revealed that training in a WM task involving a high level of adaptive forgetting specifically increased the expression of AMPA receptor GluA1 subunit and the activity of CaMKII in the dentate gyrus. These results highlight that WM with proactive interference involves mechanisms of synaptic plasticity selectively in the dentate gyrus.

Levels of Interference in Long and Short-Term Memory Differentially Modulate Non-REM and REM Sleep.

STUDY OBJECTIVES: It is commonly accepted that sleep is beneficial to memory processes, but it is still unclear if this benefit originates from improved memory consolidation or enhanced information processing. It has thus been proposed that sleep may also promote forgetting of undesirable and non-essential memories, a process required for optimization of cognitive resources. We tested the hypothesis that non-rapid eye movement sleep (NREMS) promotes forgetting of irrelevant information, more specifically when processing information in working memory (WM), while REM sleep (REMS) facilitates the consolidation of important information. METHODS: We recorded sleep patterns of rats trained in a radial maze in three different tasks engaging either the long-term or short-term storage of information, as well as a gradual level of interference. RESULTS: We observed a transient increase in REMS amount on the day the animal learned the rule of a long-term/reference memory task (RM), and, in contrast, a positive correlation between the performance of rats trained in a WM task involving an important processing of interference and the amount of NREMS or slow wave activity. Various oscillatory events were also differentially modulated by the type of training involved. Notably, NREMS spindles and REMS rapid theta increase with RM training, while sharp-wave ripples increase with all types of training. CONCLUSIONS: These results suggest that REMS, but also rapid oscillations occurring during NREMS would be specifically implicated in the long-term memory in RM, whereas NREMS and slow oscillations could be involved in the forgetting of irrelevant information required for WM.

REM Sleep-Dependent Bidirectional Regulation of Hippocampal-Based Emotional Memory and LTP.

Prolonged rapid-eye-movement (REM) sleep deprivation has long been used to study the role of REM sleep in learning and memory processes. However, this method potentially induces stress and fatigue that may directly affect cognitive functions. Here, by using a short-term and nonstressful REM sleep deprivation (RSD) method we assessed in rats the bidirectional influence of reduced and increased REM sleep amount on hippocampal-dependent emotional memory and plasticity. Our results indicate that 4 h RSD impaired consolidation of contextual fear conditioning (CFC) and induction of long-term potentiation (LTP), while decreasing density of Egr1/Zif268-expressing neurons in the CA1 region of the dorsal hippocampus. LTP and Egr1 expression were not affected in ventral CA1. Conversely, an increase in REM sleep restores and further facilitates CFC consolidation and LTP induction, and also increases Egr1 expression in dorsal CA1. Moreover, CFC consolidation, Egr1 neuron density, and LTP amplitude in dorsal CA1 show a positive correlation with REM sleep amount. Altogether, these results indicate that mild changes in REM sleep amount bidirectionally affect memory and synaptic plasticity mechanisms occurring in the CA1 area of the dorsal hippocampus.

Differential Involvement of the Dentate Gyrus in Adaptive Forgetting in the Rat.

How does the brain discriminate essential information aimed to be stored permanently from information required only temporarily, and that needs to be cleared away for not saturating our precious memory space? Reference Memory (RM) refers to the long-term storage of invariable information whereas Working Memory (WM) depends on the short-term storage of trial-unique information. Previous work has revealed that WM tasks are very sensitive to proactive interference. In order to prevent such interference, irrelevant old memories must be forgotten to give new ones the opportunity to be stabilized. However, unlike memory, physiological processes underlying this adaptive form of forgetting are still poorly understood. Here, we precisely ask what specific brain structure(s) could be responsible for such process to occur. To answer this question, we trained rats in a radial maze using three paradigms, a RM task and two WM tasks involving or not the processing of interference but strictly identical in terms of locomotion or motivation. We showed that an inhibition of the expression of Zif268 and c-Fos, two indirect markers of neuronal activity and synaptic plasticity, was observed in the dentate gyrus of the dorsal hippocampus when processing such interfering previously stored information. Conversely, we showed that inactivating the dentate gyrus impairs both RM and WM, but improves the processing of interference. Altogether, these results strongly suggest for the first time that the dentate gyrus could be a key structure involved in adaptive forgetting.

Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning.

The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning.