Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress

Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long-term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function

Making Memories: Why Time Matters

In the last decade advances in human neuroscience have identified the critical importance of time in creating long-term memories. Circadian neuroscience has established biological time functions via cellular clocks regulated by photosensitive retinal ganglion cells and the suprachiasmatic nuclei. Individuals have different circadian clocks depending on their chronotypes that vary with genetic, age, and sex. In contrast, social time is determined by time zones, daylight savings time, and education and employment hours. Social time and circadian time differences can lead to circadian desynchronization, sleep deprivation, health problems, and poor cognitive performance. Synchronizing social time to circadian biology leads to better health and learning, as demonstrated in adolescent education. In-day making memories of complex bodies of structured information in education is organized in social time and uses many different learning techniques. Research in the neuroscience of long-term memory (LTM) has demonstrated in-day time spaced learning patterns of three repetitions of information separated by two rest periods are effective in making memories in mammals and humans. This time pattern is based on the intracellular processes required in synaptic plasticity. Circadian desynchronization, sleep deprivation, and memory consolidation in sleep are less well-understood, though there has been considerable progress in neuroscience research in the last decade. The interplay of circadian, in-day and sleep neuroscience research are creating an understanding of making memories in the first 24-h that has already led to interventions that can improve health and learning

Encoding, Consolidation, and Renormalization in Depression : Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. Significance Statement-Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as N-methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.Peer reviewe

Time to Be SHY? Some Comments on Sleep and Synaptic Homeostasis

Sleep must serve an essential, universal function, one that offsets the risk of being disconnected from the environment. The synaptic homeostasis hypothesis (SHY) is an attempt to identify this essential function. Its core claim is that sleep is needed to reestablish synaptic homeostasis, which is challenged by the remarkable plasticity of the brain. In other words, sleep is “the price we pay for plasticity.” In this issue, M. G. Frank reviewed several aspects of the hypothesis and raised several issues. The comments below provide a brief summary of the motivations underlying SHY and clarify that SHY is a hypothesis not about specific mechanisms, but about a universal, essential function of sleep. This function is the preservation of synaptic homeostasis in the face of a systematic bias toward a net increase in synaptic strength—a challenge that is posed by learning during adult wake, and by massive synaptogenesis during development

Sleep slow oscillation and plasticity

It is well documented that sleep contributes to memory consolidation and it is also accepted that long-term synaptic plasticity plays a critical role in memory formation. The mechanisms of this sleep-dependent memory formation are unclear. Two main hypotheses are proposed. According to the first one, synapses are potentiated during wake; and during sleep they are scaled back to become available for the learning tasks in the next day. The other hypothesis is that sleep slow oscillations potentiate synapses that were depressed due to persistent activities during the previous day and that potentiation provides physiological basis for memory consolidation. The objective of this review is to group information on whether cortical synapses are up-scaled or down-scaled during sleep. We conclude that the majority of cortical synapses are up-regulated by sleep slow oscillation

The biological cost of consciousness

Some philosophers maintain that consciousness as subjective experience has no biological function. However, conscious brain events seem very different from unconscious ones. The cortex and thalamus support the reportable qualitative contents of consciousness. Subcortical structures like the cerebellum do not. Likewise, attended sensory stimuli are typically reportable as conscious, while memories of those stimuli are not so reportable until they are specifically recalled. 

Reports of conscious experiences in normal humans always involve subjectivity and an implicit observing ego. Unconscious brain events are not reportable, even under optimal conditions of report. While there are claimed exceptions to these points, they are rare or poorly validated. 

Normal consciousness also implies high availability (rapid conscious access) of the questions routinely asked of neurological patients in the Mental Status Examination, such as common sense features of personal identity, time, place, and social context. Along with “current concerns,” recent conscious contents, and the like, these contents correspond to high frequency items in working memory. While working memory contents are not immediately conscious, they can be rapidly re-called to consciousness. 

The anatomy and physiology of reportable conscious sensorimotor contents are ultraconserved over perhaps 200 million years of mammalian evolution. By comparison, full-fledged language is thought to arise some 100,000 years ago in homo sapiens, while writing, which enables accel-erated cultural development, dates between 2.5 and 6 millennia. Contrary to some claims, therefore, conscious waking precedes language by hundreds of millions of years. 

Like other major adaptations, conscious and unconscious brain events have distinctive biological pros and cons. These involve information processing efficiency, metabolic costs and benefits, and behavioral pros and cons. The well known momentary limited capacity of conscious contents is an example of an information processing cost, while the very large and energy-hungry corticothalamic system makes costly metabolic demands. 

After a century of scientific neglect, fundamental concepts like “conscious,” “unconscious,” “voluntary” and “non-voluntary” are still vitally important, because they refer to major biopsychological phenomena that otherwise are difficult to discuss. 
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The Role of REM Sleep in Ocular Dominance Plasticity Consolidation

Despite decades of research, the function of sleep remains controversial. One theory is that sleep plays a role in consolidating plasticity induced during prior waking. Ocular dominance plasticity (ODP) in the cat visual cortex is induced during waking monocular deprivation (MD) and consolidated during subsequent sleep. Extracellular signal-regulated kinase (ERK) signaling is required for ODP and is elevated during post-MD sleep, but its requirement during sleep is unknown. In Chapter 2, we investigated whether ERK activity is required during sleep for ODP consolidation by inhibiting the upstream activator of ERK (MEK) with intracortical infusions of U0126 into V1 during post-MD sleep. ERK inhibition abolished ODP consolidation, as measured by extracellular single unit recording. Furthermore, ERK inhibition reduced phosphorylation of eukaryotic initiation factor 4E (eIF4E) and post-synaptic density protein 95 (PSD-95) levels. MAP kinase-interacting kinase 1 (Mnk1) is activated by ERK and directly phosphorylates eIF4E; inhibition of Mnk1 mimicked the effects of ERK inhibition. These results show that activation of the ERK-Mnk1 pathway during post-MD sleep is required for ODP consolidation, and that this pathway promotes the synthesis of plasticity-related proteins such as PSD-95. However, sleep can be broadly subdivided into rapid eye movement (REM) and non-REM (NREM) sleep, but the relative contributions of these states to ODP and the ERK pathway are unknown. In Chapter 3, we examined whether REM sleep is required for ODP consolidation and ERK activation by depriving animals of REM sleep following six hours of waking MD. REM sleep deprivation (RSD) abolished ODP consolidation, as measured by optical imaging of intrinsic cortical signals, and reduced ERK phosphorylation in V1. These effects were not seen in a group that received NREM-fragmented sleep (as a control for the nonspecific effects of RSD). Furthermore, ODP and ERK phosphorylation correlated with the degree of beta-gamma activity in V1 during REM sleep, suggesting that neuronal activity patterns during REM promote ERK activation and ODP consolidation. Together, the findings in the following chapters suggest that, following the induction of cortical plasticity during waking, the ERK-Mnk1 pathway is activated during REM sleep, promoting the synthesis of plasticity-related proteins to consolidate cortical plasticity

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 slee

Use-Dependent Plasticity Regulates Sleep Need in Drosophila Melanogaster

Although the necessary functions of sleep have not been identified, sleep has been shown to play an important role in the consolidation of memories. Recent studies have shown that, in addition to playing a strong role in sleep regulation, the circadian clock also influences processes associated with learning and memory. Thus, the neural circuits that control circadian rhythms are uniquely positioned to play an important role in coordinating interactions between sleep and memory. Drosophila melanogaster exhibit increased sleep following several days of social experience and require sleep to consolidate long-term memories: LTM) after Courtship Conditioning, an associative memory assay. We have found both that changes in sleep following social experience and that memory consolidation are reliant upon the expression of plasticity-related genes in Pigment Dispersing Factor: PDF)-expressing ventral lateral neurons: LNvs), a core component of the Drosophila circadian clock. Following social enrichment, LNv projections into the medulla exhibit structural plasticity as measured by an increase in the number of synaptic terminals and that downscaling of LNv terminal number after social enrichment requires sleep. We have also found that both LNv structural plasticity and increases in sleep following social enrichment degrade with age. Importantly, restoration of mechanisms that mediate plastic responses in young flies, such as dopaminergic signaling or expression of the transcription factor blistered, restore youthful plasticity to aged flies. These data indicate that Drosophila circadian circuitry influences sleep-wake behavior in an experience-dependent manner and that proper functioning of the LNvs is required for long-term behavioral plasticity. Our observation of sleep-dependent downscaling of LNv terminals following social enrichment also indicates that an important function of sleep is to downscale potentiated synaptic connections. Together, these results establish Drosophila as a robust model system for investigating the genes and neural circuits that mediate the relationship between plasticity and sleep

Time is of the essence : Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid -acting antidepressant effects and summarize how diverse phenomena associated with ketamine's antidepressant actions - such as cortical excitation, synaptogenesis, and involved molecular determinants - are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Peer reviewe