Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity

Sleep slow wave activity (SWA) is thought to reflect sleep need, increasing after wakefulness and decreasing after sleep. We showed recently that a learning task involving a circumscribed brain region produces a local increase in sleep SWA. We hypothesized that increases in cortical SWA reflect synaptic potentiation triggered by learning. To further investigate the link between synaptic plasticity and sleep, we asked whether a procedure leading to synaptic depression would cause instead a decrease in sleep SWA. We show here that if a subject's arm is immobilized during the day, motor performance deteriorates and both somatosensory and motor evoked potentials decrease over contralateral sensorimotor cortex, indicative of local synaptic depression. Notably, during subsequent sleep, SWA over the same cortical area is markedly reduced. Thus, cortical plasticity is linked to local sleep regulation without learning in the classical sense. Moreover, when synaptic strength is reduced, local sleep need is also reduced.     

EEG sigma and slow‐wave activity during NREM sleep correlate with overnight declarative and procedural memory consolidation

Previous studies suggest that sleep‐specific brain activity patterns such as sleep spindles and electroencephalographic slow‐wave activity contribute to the consolidation of novel memories. The generation of both sleep spindles and slow‐wave activity relies on synchronized oscillations in a thalamo‐cortical network that might be implicated in synaptic strengthening (spindles) and downscaling (slow‐wave activity) during sleep. This study further examined the association between electroencephalographic power during non‐rapid eye movement sleep in the spindle (sigma, 12–16 Hz) and slow‐wave frequency range (0.1–3.5 Hz) and overnight memory consolidation in 20 healthy subjects (10 men, 27.1 ± 4.6 years). We found that both electroencephalographic sigma power and slow‐wave activity were positively correlated with the pre–post‐sleep consolidation of declarative (word list) and procedural (mirror‐tracing) memories. These results, although only correlative in nature, are consistent with the view that processes of synaptic strengthening (sleep spindles) and synaptic downscaling (slow‐wave activity) might act in concert to promote synaptic plasticity and the consolidation of both declarative and procedural memories during sleep.     

Sleep and synaptic renormalization: a computational study

Recent evidence indicates that net synaptic strength in cortical and other networks increases during wakefulness and returns to a baseline level during sleep. These homeostatic changes in synaptic strength are accompanied by corresponding changes in sleep slow wave activity (SWA) and in neuronal firing rates and synchrony. Other evidence indicates that sleep is associated with an initial reactivation of learned firing patterns that decreases over time. Finally, sleep can enhance performance of learned tasks, aid memory consolidation, and desaturate the ability to learn. Using a large-scale model of the corticothalamic system equipped with a spike-timing dependent learning rule, in agreement with experimental results, we demonstrate a net increase in synaptic strength in the waking mode associated with an increase in neuronal firing rates and synchrony. In the sleep mode, net synaptic strength decreases accompanied by a decline in SWA. We show that the interplay of activity and plasticity changes implements a control loop yielding an exponential, self-limiting renormalization of synaptic strength. Moreover, when the model "learns" a sequence of activation during waking, the learned sequence is preferentially reactivated during sleep, and reactivation declines over time. Finally, sleep-dependent synaptic renormalization leads to increased signal-to-noise ratios, increased resistance to interference, and desaturation of learning capabilities. Although the specific mechanisms implemented in the model cannot capture the variety and complexity of biological substrates, and will need modifications in line with future evidence, the present simulations provide a unified, parsimonious account for diverse experimental findings coming from molecular, electrophysiological, and behavioral approaches.     

Labile or stable: opposing consequences for memory when reactivated during waking and sleep

Memory consolidation is a dynamic process. Reconsolidation theory assumes that reactivation during wakefulness transiently destabilizes memories, requiring them to reconsolidate in order to persist. Memory reactivation also occurs during slow-wave sleep (SWS) and is assumed to underlie the consolidating effect of sleep. Here, we tested whether the same principle of transient destabilization applies to memory reactivation during SWS. We reactivated memories in humans by presenting associated odor cues either during SWS or wakefulness. Reactivation was followed by an interference task to probe memory stability. As we expected, reactivation during waking destabilized memories. In contrast, reactivation during SWS immediately stabilized memories, thereby directly increasing their resistance to interference. Functional magnetic resonance imaging revealed that reactivation during SWS mainly activated hippocampal and posterior cortical regions, whereas reactivation during wakefulness primarily activated prefrontal cortical areas. Our results show that reactivation of memory serves distinct functions depending on the brain state of wakefulness or sleep.     

Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves

STUDY OBJECTIVES: Sleep slow-wave activity (SWA, electroencephalogram [EEG] power between 0.5 and 4.0 Hz) is homeostatically regulated, increasing with wakefulness and declining with sleep. Sleep SWA is thought to reflect sleep need, but the mechanisms of its homeostatic regulation remain unknown. Based on a recent hypothesis, we sought to determine whether a decrease in cortical synaptic strength can account for changes in sleep SWA. DESIGN: A large-scale computer model of the sleeping thalamocortical system was used to reproduce in detail the cortical slow oscillations underlying EEG slow waves. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: Simulated reductions in the strength of corticocortical synapses. MEASUREMENTS AND RESULTS: Decreased synaptic strength led to (1) decreased single cell membrane potential oscillations and reduced network synchronization, (2) decreased rate of neural recruitment and decruitment, and (3) emergence of local clusters of synchronized activity. These changes were reflected in the local EEG as (1) decreased incidence of high-amplitude slow waves, (2) decreased wave slope, and (3) increased number of multipeak waves. Spectral analysis confirmed that these changes were associated with a decrease in SWA. CONCLUSIONS: A decrease in cortical synaptic strength is sufficient to account for changes in sleep SWA and is accompanied by characteristic changes in slow-wave parameters. Experimental results from rat cortical depth recordings and human high-density EEG show similar changes in slow-wave parameters with decreasing SWA, suggesting that the underlying mechanism may indeed be a net decrease in synaptic strength.     

Induction of long-term potentiation leads to increased reliability of evoked neocortical spindles in vivo

Large amplitude electroencephalographic spindle waves (7-14 Hz) occur spontaneously in the neocortex during both sleep and awake immobility, and it has been proposed that synchronous neuronal activation during spindles may contribute to learning-related synaptic plasticity. Spindles can also be evoked in the sensorimotor cortex by electrical stimulation of cortical or thalamic inputs in the rat. To determine if strengthening cortical synapses can affect the initiation and maintenance of electrically evoked spindles, stimulation pulses were delivered at a range of intensities to the corpus callosum or ventrolateral thalamus in the awake rat before and after the induction of long-term potentiation (LTP) by tetanization of the corpus callosum. The morphology of evoked spindles was similar to that of naturally occurring spindles. Spindles were evoked less reliably during slow-wave sleep than during waking, and this was correlated with smaller synaptic responses during slow-wave sleep. Similar to previous findings, daily tetanization of the corpus callosum for 15 days decreased the early component and increased the late component of synaptic responses evoked by corpus callosum stimulation, but did not significantly affect synaptic responses evoked by thalamic stimulation. Similarly, LTP induction increased the reliability with which low-intensity corpus callosum stimulation evoked spindles, but increases in spindles evoked by thalamic stimulation were not significant. Synaptic potentiation and the increased reliability of spindles developed with a similar time-course over the 15-day LTP induction period. These results reflect strong correlations between the strength of cortical layer V activation and the initiation of spindles in the sensorimotor cortex, and support the idea that monosynaptic and polysynaptic horizontal collaterals of layer V neurons can play a significant role in the initiation of spindles.     

Spontaneous slow oscillation—slow spindle features predict induced overnight memory retention

Study ObjectivesSynchronization of neural activity within local networks and between brain regions is a major contributor to rhythmic field potentials such as the EEG. On the other hand, dynamic changes in microstructure and activity are reflected in the EEG, for instance slow oscillation (SO) slope can reflect synaptic strength. SO-spindle coupling is a measure for neural communication. It was previously associated with memory consolidation, but also shown to reveal strong interindividual differences. In studies, weak electric current stimulation has modulated brain rhythms and memory retention. Here, we investigate whether SO-spindle coupling and SO slope during baseline sleep are associated with (predictive of) stimulation efficacy on retention performance.MethodsTwenty-five healthy subjects participated in three experimental sessions. Sleep-associated memory consolidation was measured in two sessions, in one anodal transcranial direct current stimulation oscillating at subjects individual SO frequency (so-tDCS) was applied during nocturnal sleep. The third session was without a learning task (baseline sleep). The dependence on SO-spindle coupling and SO-slope during baseline sleep of so-tDCS efficacy on retention performance were investigated.ResultsStimulation efficacy on overnight retention of declarative memories was associated with nesting of slow spindles to SO trough in deep nonrapid eye movement baseline sleep. Steepness and direction of SO slope in baseline sleep were features indicative for stimulation efficacy.ConclusionsFindings underscore a functional relevance of activity during the SO up-to-down state transition for memory consolidation and provide support for distinct consolidation mechanisms for types of declarative memories.     

Synaptic depression in visual cortex tissue slices: an in vitro model for cortical neuron adaptation

Synaptic depression was assessed from intracellular recordings in cortical tissue slices. Evoked postsynaptic potentials exhibited synaptic depression with an exponential or double exponential decrease (time constants: <1–30 s) in amplitude during repetitive afferent stimulation by short trains of suprathreshold stimuli. Depressed synaptic responses recovered with an exponential time course (time constants: 10 s-8 min) during presentation of similar short trains of stimuli every 5 or 10 s. Cortical cells recorded extracellularly in cat visual cortex show similar time constants of response decrement during adaptation to moving stripes. Postsynaptic voltage- or ion-regulated conductances and chloride conductances do not appear to be involved in synaptic depression. Input resistance changes and effects of injection of chloride indicate a lack of GABA_A receptor-mediated effects. Hyperpolarizing or depolarizing neurons, and pairing polarization with afferent stimulation, also did not affect synaptic depression. This distinguishes these processes from long-term depression and long-term potentiation. Our results suggest that the most likely mechanisms of synaptic depression and adaptation in cortical cells are presynaptic decrease in transmitter release and/or receptor desensitization. Short-term postsynaptic changes may also occur after synaptic depression.     

Modeling sleep and wakefulness in the thalamocortical system

When the brain goes from wakefulness to sleep, cortical neurons begin to undergo slow oscillations in their membrane potential that are synchronized by thalamocortical circuits and reflected in EEG slow waves. To provide a self-consistent account of the transition from wakefulness to sleep and of the generation of sleep slow waves, we have constructed a large-scale computer model that encompasses portions of two visual areas and associated thalamic and reticular thalamic nuclei. Thousands of model neurons, incorporating several intrinsic currents, are interconnected with millions of thalamocortical, corticothalamic, and both intra- and interareal corticocortical connections. In the waking mode, the model exhibits irregular spontaneous firing and selective responses to visual stimuli. In the sleep mode, neuromodulatory changes lead to slow oscillations that closely resemble those observed in vivo and in vitro. A systematic exploration of the effects of intrinsic currents and network parameters on the initiation, maintenance, and termination of slow oscillations shows the following. 1) An increase in potassium leak conductances is sufficient to trigger the transition from wakefulness to sleep. 2) The activation of persistent sodium currents is sufficient to initiate the up-state of the slow oscillation. 3) A combination of intrinsic and synaptic currents is sufficient to maintain the up-state. 4) Depolarization-activated potassium currents and synaptic depression terminate the up-state. 5) Corticocortical connections synchronize the slow oscillation. The model is the first to integrate intrinsic neuronal properties with detailed thalamocortical anatomy and reproduce neural activity patterns in both wakefulness and sleep, thereby providing a powerful tool to investigate the role of sleep in information transmission and plasticity.     

The effect of daytime napping and full‐night sleep on the consolidation of declarative and procedural information

Many studies investigating sleep and memory consolidation have evaluated full‐night sleep rather than alternative sleep periods such as daytime naps. This multi‐centre study followed up on, and was compared with, an earlier full‐night study (Schabus et al., 2004) investigating the relevance of daytime naps for the consolidation of declarative and procedural memory. Seventy‐six participants were randomly assigned to a nap or wake group, and performed a declarative word‐pair association or procedural mirror‐tracing task. Performance changes from before to after a 90‐min retention interval filled with sleep or quiet wakefulness were evaluated between groups. Associations between performance changes, sleep architecture, spindles, and slow oscillations were investigated. For the declarative task we observed a trend towards stronger forgetting across a wake period compared with a nap period, and a trend towards memory increase over the full‐night. For the procedural task, accuracy was significantly decreased following daytime wakefulness, showed a trend to increase with a daytime nap, and significantly increased across full‐night sleep. For the nap protocol, neither sleep stages, spindles, nor slow oscillations predicted performance changes. A direct comparison of day and nighttime sleep revealed that daytime naps are characterized by significantly lower spindle density, but higher spindle activity and amplitude compared with full‐night sleep. In summary, data indicate that daytime naps protect procedural memories from deterioration, whereas full‐night sleep improves performance. Given behavioural and physiological differences between day and nighttime sleep, future studies should try to characterize potential differential effects of full‐night and daytime sleep with regard to sleep‐dependent memory consolidation.     

Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal-prefrontal cortex pathway of rats in vivo: a possible involvement of monoaminergic systems

The prefrontal cortex is continuously required for working memory processing during wakefulness, but is particularly hypoactivated during sleep and in psychiatric disorders such as schizophrenia. Ammon's horn CA1 hippocampus subfield (CA1) afferents provide a functional modulatory path that is subjected to synaptic plasticity and a prominent monoaminergic influence. However, little is known about the muscarinic cholinergic effects on prefrontal synapses. Here, we investigated the effects of the muscarinic agonist, pilocarpine (PILO), on the induction and maintenance of CA1-medial prefrontal cortex (mPFC) long-term potentiation (LTP) as well as on brain monoamine levels. Field evoked responses were recorded in urethane-anesthetized rats during baseline (50 min) and after LTP (130 min), and compared with controls. LTP was induced 20 min after PILO administration (15 mg/kg, i.p.) or vehicle (NaCl 0.15 M, i.p.). In a separate group of animals, the hippocampus and mPFC were microdissected 20 min after PILO injection and used to quantify monoamine levels. Our results show that PILO potentiates the late-phase of mPFC LTP without affecting either post-tetanic potentiation or early LTP (20 min). This effect was correlated with a significant decrease in relative delta (1-4 Hz) power and an increase in sigma (10-15 Hz) and gamma (25-40 Hz) powers in CA1. Monoamine levels were specifically altered in the mPFC. We observed a decrease in dopamine, 5-HT, 5-hydroxyindolacetic acid and noradrenaline levels, with no changes in 3,4-hydroxyphenylacetic acid levels. Our data, therefore, suggest that muscarinic activation exerts a boosting effect on mPFC synaptic plasticity and possibly on mPFC-dependent memories, associated to monoaminergic changes.     

Effects of Skilled Training on Sleep Slow Wave Activity and Cortical Gene Expression in the Rat

Study Objective:

The best characterized marker of sleep homeostasis is the amount of slow wave activity (SWA, 0.5–4 Hz) during NREM sleep. SWA increases as a function of previous waking time and declines during sleep, but the underlying mechanisms remain unclear. We have suggested that SWA homeostasis is linked to synaptic potentiation associated with learning during wakefulness. Indeed, studies in rodents and humans found that SWA increases after manipulations that presumably enhance synaptic strength, but the evidence remains indirect. Here we trained rats in skilled reaching, a task known to elicit long-term potentiation in the trained motor cortex, and immediately after learning measured SWA and cortical protein levels of c-fos and Arc, 2 activity-dependent genes involved in motor learning.

Design:

Intracortical local field potential recordings and training on reaching task.

Setting:

Basic sleep research laboratory.

Patients or Participants:

Long Evans adult male rats.

Interventions:

N/A

Measurements and Results:

SWA increased post-training in the trained cortex (the frontal cortex contralateral to the limb used to learn the task), with smaller or no increase in other cortical areas. This increase was reversible within 1 hour, specific to NREM sleep, and positively correlated with changes in performance during the prior training session, suggesting that it reflects plasticity and not just motor activity. Fos and Arc levels were higher in the trained relative to untrained motor cortex immediately after training, but this asymmetry was no longer present after 1 hour of sleep.

Conclusion:

Learning to reach specifically affects gene expression in the trained motor cortex and, in the same area, increases sleep need as measured by a local change in SWA.

Citation:

Hanlon EC; Faraguna U; Vyazovskiy VV; Tononi G; Cirelli C. Effects of skilled training on sleep slow wave activity and cortical gene expression in the rat. SLEEP 2009;32(6):719-729.     

Sleep enhances inhibitory behavioral control in discrimination learning in rats

Sleep supports the consolidation of memory, and it has been proposed that this enhancing effect of sleep pertains in particular to memories which are encoded under control of prefrontal–hippocampal circuitry into an episodic memory system. Furthermore, repeated reactivation and transformation of such memories during sleep are thought to promote the de-contextualization of these memories. Here, we aimed to establish a behavioral model for the study of such sleep-dependent system consolidation in rats, using a go/nogo conditional discrimination learning task known to essentially depend on prefrontal–hippocampal function. Different groups of rats were trained to criterion on this task and, then, subjected to 80-min retention intervals filled with spontaneous morning sleep, sleep deprivation, or spontaneous evening wakefulness. In a subsequent test phase, the speed of relearning of the discrimination task was examined as indicator of memory, whereby rats were either tested in the same context as during training or in a different context. Sleep promoted relearning of the conditional discrimination task, and this effect was similar for testing memory in the same or different context (p < 0.001). Independent of sleep and wakefulness during the retention interval, animals showed faster relearning when tested in the same context as during learning, compared with testing in a different context (p < 0.001). The benefitting effect of sleep on discrimination learning was primarily due to an enhancing effect on response suppression during the nogo stimulus. We infer from these results that sleep enhances memory for inhibitory behavioral control in a generalized context-independent manner and thereby might eventually also contribute to the abstraction of schema-like representations.     

Sleep and plasticity

While there is ample agreement that the cognitive role of sleep is explained by sleep-dependent synaptic changes, consensus is yet to be established as to the nature of these changes. Some researchers believe that sleep promotes global synaptic downscaling, leading to a non-Hebbian reset of synaptic weights that is putatively necessary for the acquisition of new memories during ensuing waking. Other investigators propose that sleep also triggers experience-dependent, Hebbian synaptic upscaling able to consolidate recently acquired memories. Here, I review the molecular and physiological evidence supporting these views, with an emphasis on the calcium signaling pathway. I argue that the available data are consistent with sleep promoting experience-dependent synaptic embossing, understood as the simultaneous non-Hebbian downscaling and Hebbian upscaling of separate but complementary sets of synapses, heterogeneously activated at the time of memory encoding and therefore differentially affected by sleep.     

Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats

Prolonged wakefulness or a lack of sleep lead to cognitive deficits, but little is known about the underlying cellular mechanisms. We recently found that sleep deprivation affects spontaneous neuronal activity in the neocortex of sleeping and awake rats. While it is well known that synaptic responses are modulated by ongoing cortical activity, it remains unclear whether prolonged waking affects responsiveness of cortical neurons to incoming stimuli. By applying local electrical microstimulation to the frontal area of the neocortex, we found that after a 4 h period of waking the initial neuronal response in the contralateral frontal cortex was stronger and more synchronous, and was followed by a more profound inhibition of neuronal spiking as compared with the control condition. These changes in evoked activity suggest increased neuronal excitability and indicate that, after staying awake, cortical neurons become transiently bistable. We propose that some of the detrimental effects of sleep deprivation may be a result of altered neuronal responsiveness to incoming intrinsic and extrinsic inputs.     

Synaptic plasticity in the subiculum

The subiculum is the principal target of CA1 pyramidal cells. It functions as a mediator of hippocampal–cortical interaction and has been proposed to play an important role in the encoding and retrieval of long-term memory. The cellular mechanisms of memory formation are thought to include long-term potentiation (LTP) and depression (LTD) of synaptic strength. This review summarizes the contemporary knowledge of LTP and LTD at CA1–subiculum synapses. The observation that the underlying mechanisms of LTP and LTD at CA1–subiculum synapses correlate with the discharge properties of subicular pyramidal cell reveals a novel and intriguing mechanism of cell-specific consolidation of hippocampal output.     

Control of sleep and wakefulness

This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.     

Why does serotonergic activity drastically decrease during REM sleep?

Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep–wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation.     

Offline consolidation of procedural skill learning is enhanced by negative emotional content

It is now well established that both procedural skills and episodic memories consolidate across periods of offline retention, and most particularly across periods of sleep. Such consolidation has been demonstrated to be more marked for emotional than for neutral episodes, but the interaction between emotionality and the offline consolidation of procedural skills has yet to be investigated. Here, we address this issue by examining the impact of an emotional background context at encoding upon the subsequent consolidation of mirror tracing, a well-studied procedural skill. We also consider the importance of sleep for such consolidation by manipulating the retention interval (over a day, overnight, or over 24 h containing normal sleep). Our data show significantly greater offline improvements in the accuracy of mirror tracing when negative emotional content is present during the training phase when compared to when neutral or positive content is present. Furthermore, consolidation across a night of sleep is associated with faster and more accurate performance than consolidation across a day of wakefulness. These novel findings show that the emotional context in which a procedural skill is learned can impact upon subsequent offline consolidation.     

Synaptic plasticity in the subiculum

The subiculum is the principal target of CA1 pyramidal cells. It functions as a mediator of hippocampal–cortical interaction and has been proposed to play an important role in the encoding and retrieval of long-term memory. The cellular mechanisms of memory formation are thought to include long-term potentiation (LTP) and depression (LTD) of synaptic strength. This review summarizes the contemporary knowledge of LTP and LTD at CA1–subiculum synapses. The observation that the underlying mechanisms of LTP and LTD at CA1–subiculum synapses correlate with the discharge properties of subicular pyramidal cell reveals a novel and intriguing mechanism of cell-specific consolidation of hippocampal output.