Chronic sleep deprivation differentially affects short and long-term operant memory in Aplysia.
ABSTRACT: The induction, formation and maintenance of memory represent dynamic processes modulated by multiple factors including the circadian clock and sleep. Chronic sleep restriction has become common in modern society due to occupational and social demands. Given the impact of cognitive impairments associated with sleep deprivation, there is a vital need for a simple animal model in which to study the interactions between chronic sleep deprivation and memory. We used the marine mollusk Aplysia californica, with its simple nervous system, nocturnal sleep pattern and well-characterized learning paradigms, to assess the effects of two chronic sleep restriction paradigms on short-term (STM) and long-term (LTM) associative memory. The effects of sleep deprivation on memory were evaluated using the operant learning paradigm, learning that food is inedible, in which the animal associates a specific netted seaweed with failed swallowing attempts. We found that two nights of 6h sleep deprivation occurring during the first or last half of the night inhibited both STM and LTM. Moreover, the impairment in STM persisted for more than 24h. A milder, prolonged sleep deprivation paradigm consisting of 3 consecutive nights of 4h sleep deprivation also blocked STM, but had no effect on LTM. These experiments highlight differences in the sensitivity of STM and LTM to chronic sleep deprivation. Moreover, these results establish Aplysia as a valid model for studying the interactions between chronic sleep deprivation and associative memory paving the way for future studies delineating the mechanisms through which sleep restriction affects memory formation.
Project description:Insufficient sleep in individuals appears increasingly common due to the demands of modern work schedules and technology use. Consequently, there is a growing need to understand the interactions between sleep deprivation and memory. The current study determined the effects of acute sleep deprivation on short and long-term associative memory using the marine mollusk Aplysia californica, a relatively simple model system well known for studies of learning and memory.Aplysia were sleep deprived for 9 hours using context changes and tactile stimulation either prior to or after training for the operant learning paradigm, learning that food is inedible (LFI). The effects of sleep deprivation on short-term (STM) and long-term memory (LTM) were assessed.Acute sleep deprivation prior to LFI training impaired the induction of STM and LTM with persistent effects lasting at least 24 h. Sleep deprivation immediately after training blocked the consolidation of LTM. However, sleep deprivation following the period of molecular consolidation did not affect memory recall. Memory impairments were independent of handling-induced stress, as daytime handled control animals demonstrated no memory deficits. Additional training immediately after sleep deprivation failed to rescue the induction of memory, but additional training alleviated the persistent impairment in memory induction when training occurred 24 h following sleep deprivation.Acute sleep deprivation inhibited the induction and consolidation, but not the recall of memory. These behavioral studies establish Aplysia as an effective model system for studying the interactions between sleep and memory formation.
Project description:Behavioral research has yielded conflicting results regarding the architecture of short-term memory (STM). Whereas a consensus has emerged that within STM a single chunk within the focus of attention (FA) has a privileged status, it is unclear whether further distinctions exist. One proposal is that outside of FA, memory is all of one sort with a continuous progression from STM to long-term memory (LTM). On the other hand, sharp performance drop-offs when STM is loaded with more than 4±1 items suggest distinctions between STM and LTM. We use functional magnetic resonance imaging (fMRI) to adjudicate between these theories. A neural triple dissociation provided evidence for a 3-state model of memory. Critically, prefrontal cortex was selectively enhanced to retrieval from activated portions of LTM whereas the hippocampus was associated with retrieval of items within putative 4±1 capacity limits. We hypothesize that the associative properties of the hippocampus serve to inter-relate information actively maintained in STM which not only promotes strong STM, but also lays the foundations for subsequent LTM. By contrast, information not actively maintained in mind requires top-down retrieval processes mediated by the prefrontal cortex. These data provide key insights into the architecture of STM and its relationship to LTM.
Project description:Because of the relative simplicity of its nervous system, Caenorhabditis elegans is a useful model organism to study learning and memory at cellular and molecular levels. For appetitive conditioning in C. elegans, food has exclusively been used as an unconditioned stimulus (US). It may be difficult to analyze neuronal circuits for associative memory since food is a multimodal combination of olfactory, gustatory, and mechanical stimuli. Here, we report classical appetitive conditioning and associative memory in C. elegans, using 1-nonanol as a conditioned stimulus (CS), and potassium chloride (KCl) as a US. Before conditioning, C. elegans innately avoided 1-nonanol, an aversive olfactory stimulus, and was attracted by KCl, an appetitive gustatory stimulus, on assay agar plates. Both massed training without an intertrial interval (ITI) and spaced training with a 10-min ITI induced significant levels of memory of association regarding the two chemicals. Memory induced by massed training decayed within 6 h, while that induced by spaced training was retained for more than 6 h. Animals treated with inhibitors of transcription or translation formed the memory induced by spaced training less efficiently than untreated animals, whereas the memory induced by massed training was not significantly affected by such treatments. By definition, therefore, memories induced by massed training and spaced training are classified as short-term memory (STM) and long-term memory (LTM), respectively. When animals conditioned by spaced training were exposed to 1-nonanol alone, their learning index was lower than that of untreated animals, suggesting that extinction learning occurs in C. elegans. In support of these results, C. elegans mutants defective in nmr-1, encoding an NMDA receptor subunit, formed both STM and LTM less efficiently than wild-type animals, while mutations in crh-1, encoding a ubiquitous transcription factor CREB required for memory consolidation, affected LTM, but not STM. The paradigm established in the present study should allow us to elucidate neuronal circuit plasticity for appetitive learning and memory in C. elegans.
Project description:Sleep is thought to be important for memory consolidation, since sleep deprivation has been shown to interfere with memory processing. However, the effects of augmenting sleep on memory formation are not well known, and testing the role of sleep in memory enhancement has been limited to pharmacological and behavioral approaches. Here we test the effect of overexpressing the brain-type fatty acid binding protein (Fabp7) on sleep and long-term memory (LTM) formation in Drosophila melanogaster. Transgenic flies carrying the murine Fabp7 or the Drosophila homologue dFabp had reduced baseline sleep but normal LTM, while Fabp induction produced increases in both net sleep and LTM. We also define a post-training consolidation "window" that is sufficient for the observed Fabp-mediated memory enhancement. Since Fabp overexpression increases consolidated daytime sleep bouts, these data support a role for longer naps in improving memory and provide a novel role for lipid-binding proteins in regulating memory consolidation concurrently with changes in behavioral state.
Project description:In addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term operant memory formation using the learning that food is inedible (LFI) paradigm. A single LFI training session, in which the animal associates a specific netted seaweed with the failure to swallow, generates short (30min), intermediate (4-6h) and long-term (24h) memory. Using the calpain inhibitors calpeptin and MDL-28170, we found that ITM requires calpain activity for induction and consolidation similar to the previously reported requirements for persistent protein kinase C activity in intermediate-term LFI memory. The induction of LTM also required calpain activity. In contrast to ITM, calpain activity was not necessary for the molecular consolidation of LTM. Surprisingly, six hours after LFI training we found that calpain activity was necessary for LTM, although this is a time at which neither persistent PKC activity nor protein synthesis is required for the maintenance of long-term LFI memory. These results demonstrate that calpains function in multiple roles in vivo during associative memory formation.
Project description:As chronic sleep restriction is a widespread problem among adolescents, the present study investigated the effects of a 1-week sleep restriction (SR) versus control period on the consolidation of long-term memory for prose passages. We also determined whether the benefit of prioritization on memory is modulated by adequate sleep occurring during consolidation. Fifty-six healthy adolescents (25 male, aged 15-19 years) were instructed to remember a prose passage in which half of the content was highlighted (prioritized), and were told that they would receive an additional bonus for remembering highlighted content. Following an initial free recall test, participants underwent a 7-night period in which they received either a 5-h (SR) or 9-h (control) nightly sleep opportunity, monitored by polysomnography on selected nights. Free recall of the passage was tested at the end of the sleep manipulation period (1 week after encoding), and again 6 weeks after encoding. Recall of highlighted content was superior to that of non-highlighted content at all three time-points (initial, 1 week, 6 weeks). This beneficial effect of prioritization on memory was stronger 1 week relative to a few minutes after encoding for the control, but not the SR group. N3 duration was similar in the control and SR groups. Overall, the present study shows that the benefits of prioritization on memory are enhanced over time, requiring time and sleep to unfold fully. Partial sleep deprivation (i.e. 5-h nocturnal sleep opportunity) may attenuate such benefits, but this may be offset by preservation of N3 sleep duration.
Project description:Accumulating evidence suggests a critical role for epigenetic regulations in long term memory (LTM) formation. Among them, post-translational modifications of proteins, as histone acetylation, are an important regulator of chromatin remodelling and gene transcription. While the implication of histone acetylation in memory consolidation is widely accepted, less is known about its role in memory reconsolidation i.e. during memory restabilization after its reactivation. In the present study, we investigated the role of histone acetylation during the initial consolidation and the reconsolidation of spatial memory, using a weak massed learning procedure in the Morris water maze paradigm in mice. Usually a weak learning is sufficient for short term memory (STM) formation, but insufficient to upgrade STM to LTM. We found that promoting histone acetylation through intra-hippocampal infusion of a class I selective histone deacetylase (HDAC) inhibitor immediately after a subthreshold spatial learning improved LTM but not STM retention. More importantly, inhibiting HDAC activity after the reactivation of a weak memory promoted specifically LTM reconsolidation without affecting post-reactivation STM. These findings argue in favour of an important role for histone acetylation in memory consolidation, and more particularly during the reconsolidation of spatial memory in mice.
Project description:To investigate the effects of sleep restriction (7 nights of 5 h time in bed [TIB]) on cognitive performance, subjective sleepiness, and mood in adolescents.A parallel-group design was adopted in the Need for Sleep Study. Fifty-six healthy adolescents (25 males, age = 15-19 y) who studied in top high schools and were not habitual short sleepers were randomly assigned to Sleep Restriction (SR) or Control groups. Participants underwent a 2-w protocol consisting of 3 baseline nights (TIB = 9 h), 7 nights of sleep opportunity manipulation (TIB = 5 h for the SR and 9 h for the control groups), and 3 nights of recovery sleep (TIB = 9 h) at a boarding school. A cognitive test battery was administered three times each day.During the manipulation period, the SR group demonstrated incremental deterioration in sustained attention, working memory and executive function, increase in subjective sleepiness, and decrease in positive mood. Subjective sleepiness and sustained attention did not return to baseline levels even after 2 recovery nights. In contrast, the control group maintained baseline levels of cognitive performance, subjective sleepiness, and mood throughout the study. Incremental improvement in speed of processing, as a result of repeated testing and learning, was observed in the control group but was attenuated in the sleep-restricted participants, who, despite two recovery sleep episodes, continued to perform worse than the control participants.A week of partial sleep deprivation impairs a wide range of cognitive functions, subjective alertness, and mood even in high-performing high school adolescents. Some measures do not recover fully even after 2 nights of recovery sleep.A commentary on this article appears in this issue on page 497.
Project description:Given the role that sleep plays in modulating plasticity, we hypothesized that increasing sleep would restore memory to canonical memory mutants without specifically rescuing the causal molecular lesion. Sleep was increased using three independent strategies: activating the dorsal fan-shaped body, increasing the expression of Fatty acid binding protein (dFabp), or by administering the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Short-term memory (STM) or long-term memory (LTM) was evaluated in rutabaga (rut) and dunce (dnc) mutants using aversive phototaxic suppression and courtship conditioning. Each of the three independent strategies increased sleep and restored memory to rut and dnc mutants. Importantly, inducing sleep also reverses memory defects in a Drosophila model of Alzheimer's disease. Together, these data demonstrate that sleep plays a more fundamental role in modulating behavioral plasticity than previously appreciated and suggest that increasing sleep may benefit patients with certain neurological disorders.
Project description:Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimer's disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM.