Synaptic Downscaling Research Articles

Sleep induced by mechanosensory stimulation provides cognitive and health benefits in Drosophila.

Sleep is a complex phenomenon regulated by various factors, including sensory input. Anecdotal observations have suggested that gentle rocking helps babies fall asleep, and experimental studies have verified that rocking promotes sleep in both humans and mice. Recent studies have expanded this understanding, demonstrating that gentle vibration also induces sleep in Drosophila. Natural sleep serves multiple functions, including learning and memory, synaptic downscaling, and clearance of harmful substances associated with neurodegenerative diseases. Here, we investigated whether vibration-induced sleep provides similar cognitive and health benefits in Drosophila. We administered gentle vibration to flies that slept very little due to a forced activation of wake-promoting neurons and investigated how the vibration influenced learning and memory in the courtship conditioning paradigm. Additionally, we examined the effects of VIS on synaptic downscaling by counting synapse numbers of select neurons. Finally, we determined whether vibration could induce sleep in Drosophila models of Alzheimer's disease (AD) and promote the clearance of Amyloid b (Ab) and Tubulin Associated Unit (TAU). Vibration-induced sleep enhanced performance in a courtship conditioning paradigm and reduced the number of synapses in select neurons. Moreover, vibration improved sleep in Drosophila models of AD, promoting the clearance of Ab and TAU. Mechanosensory stimulation offers a promising non-invasive avenue for enhancing sleep, potentially providing associated cognitive and health benefits.

Perivascular space diffusivity and brain microstructural measures are associated with circadian time and sleep quality.

The glymphatic system is centred around brain cerebrospinal fluid flow and is enhanced during sleep, and the synaptic homeostasis hypothesis proposes that sleep acts on brain microstructure by selective synaptic downscaling. While so far primarily studied in animals, we here examine in humans if brain diffusivity and microstructure is related to time of day, sleep quality and cognitive performance. We use diffusion weighted images from 916 young healthy individuals, aged between 22 and 37 years, collected as part of the Human Connectome Project to assess diffusion tensor image analysis along the perivascular space index, white matter fractional anisotropy, intra-neurite volume fraction and extra-neurite mean diffusivity. Next, we examine if these measures are associated with circadian time of acquisition, the Pittsburgh Sleep Quality Index (high scores correspond to low sleep quality) and age-adjusted cognitive function total composite score. Consistent with expectations, we find that diffusion tensor image analysis along the perivascular space index and orbitofrontal grey matter extra-neurite mean diffusivity are negatively and white matter fractional anisotropy positively correlated with circadian time. Further, we find that grey matter intra-neurite volume fraction correlates positively with Pittsburgh Sleep Quality Index, and that this correlation is driven by sleep duration. Finally, we find positive correlations between grey matter intra-neurite volume fraction and cognitive function total composite score, as well as negative interaction effects between cognitive function total composite score and Pittsburgh Sleep Quality Index on grey matter intra-neurite volume fraction. Our findings propose that perivascular flow is under circadian control and that sleep downregulates the intra-neurite volume in healthy adults with positive impact on cognitive function.

ABHD6 drives endocytosis of AMPA receptors to regulate synaptic plasticity and learning flexibility

Trafficking of α‐Amino‐3–hydroxy‐5–methylisoxazole‐4–propionic acid (AMPA) receptors (AMPARs), mediated by AMPAR interacting proteins, enabled neurons to maintain tuning capabilities at rest or active state. α/β-Hydrolase domain-containing 6 (ABHD6), an endocannabinoid hydrolase, was an AMPAR auxiliary subunit found to negatively regulate the surface delivery of AMPARs. While ABHD6 was found to prevent AMPAR tetramerization in endoplasmic reticulum, ABHD6 was also reported to localize at postsynaptic site. Yet, the role of ABHD6 interacting with AMPAR at postsynaptic site, and the physiological significance of ABHD6 regulating AMPAR trafficking remains elusive. Here, we generated the ABHD6 knockout (ABHD6KO) mice and found that deletion of ABHD6 selectively enhanced AMPAR-mediated basal synaptic responses and the surface expression of postsynaptic AMPARs. Furthermore, we found that loss of ABHD6 impaired hippocampal long-term depression (LTD) and synaptic downscaling in hippocampal synapses. AMPAR internalization assays revealed that ABHD6 was essential for neuronal activity-dependent endocytosis of surface AMPARs, which is independent of ABHD6's hydrolase activity. The defects of AMPAR endocytosis and LTD are expressed as deficits in learning flexibility in ABHD6KO mice. Collectively, we demonstrated that ABHD6 is an endocytic accessory protein promoting AMPAR endocytosis, thereby contributes to the formation of LTD, synaptic downscaling and reversal learning.

Slow wave activity across sleep-night could predict levodopa-induced dyskinesia

A disruption in the slow wave activity (SWA) mediated synaptic downscaling process features Parkinson's disease (PD) patients presenting levodopa-induced dyskinesia (LID). To corroborate the role of SWA in LID development, 15 PD patients with LID, who underwent a polysomnography before LID’s appearance, were included. Slow wave sleep epochs were extracted, combined and segmented into early and late sleep. SWA power was calculated. A linear regression model established that the SWA overnight decrease could predict the time to the emergence of LID. Our finding supports the link between SWA-mediated synaptic downscaling and the development of LID. If confirmed, it could pave the way to the study of possible sleep targeted therapies able to protect PD patients from LID development.

The kinesin Kif21b binds myosin Va and mediates changes in actin dynamics underlying homeostatic synaptic downscaling

Homeostatic synaptic plasticity adjusts the strength of synapses to restrain neuronal activity within a physiological range. Postsynaptic guanylate kinase-associated protein (GKAP) controls the bidirectional synaptic scaling of AMPA receptors (AMPARs); however, mechanisms by which chronic activity triggers cytoskeletal remodeling to downscale synaptic transmission are barely understood. Here, we report that the microtubule-dependent kinesin motor Kif21b binds GKAP and likewise is located in dendritic spines in a myosin Va- and neuronal-activity-dependent manner. Kif21b depletion unexpectedly alters actin dynamics in spines, and adaptation of actin turnover following chronic activity is lost in Kif21b-knockout neurons. Consistent with a role of the kinesin in regulating actin dynamics, Kif21b overexpression promotes actin polymerization. Moreover, Kif21b controls GKAP removal from spines and the decrease of GluA2-containing AMPARs from the neuronal surface, thereby inducing homeostatic synaptic downscaling. Our data highlight a critical role of Kif21b at the synaptic actin cytoskeleton underlying homeostatic scaling of neuronal firing.

Regulation of dendritic spines in the amygdala following sleep deprivation.

The amygdala is a hub of emotional circuits involved in the regulation of cognitive and emotional behaviors and its critically involved in emotional reactivity, stress regulation, and fear memory. Growing evidence suggests that the amygdala plays a key role in the consolidation of emotional memories during sleep. Neuroimaging studies demonstrated that the amygdala is selectively and highly activated during rapid eye movement sleep (REM) and sleep deprivation induces emotional instability and dysregulation of the emotional learning process. Regulation of dendritic spines during sleep represents a morphological correlate of memory consolidation. Several studies indicate that dendritic spines are remodeled during sleep, with evidence for broad synaptic downscaling and selective synaptic upscaling in several cortical areas and the hippocampus. Currently, there is a lack of information regarding the regulation of dendritic spines in the amygdala during sleep. In the present work, we investigated the effect of 5 h of sleep deprivation on dendritic spines in the mouse amygdala. Our data demonstrate that sleep deprivation results in differential dendritic spine changes depending on both the amygdala subregions and the morphological subtypes of dendritic spines. We observed decreased density of mushroom spines in the basolateral amygdala of sleep deprived mice, together with increased neck length and decreased surface area and volume. In contrast, we observed greater densities of stubby spines in sleep deprived mice in the central amygdala, indicating that downscaling selectively occurs in this spine type. Greater neck diameters for thin spines in the lateral and basolateral nuclei of sleep deprived mice, and decreases in surface area and volume for mushroom spines in the basolateral amygdala compared to increases in the cental amygdala provide further support for spine type-selective synaptic downscaling in these areas during sleep. Our findings suggest that sleep promotes synaptic upscaling of mushroom spines in the basolateral amygdala, and downscaling of selective spine types in the lateral and central amygdala. In addition, we observed decreased density of phosphorylated cofilin immunoreactive and growth hormone immunoreactive cells in the amygdala of sleep deprived mice, providing further support for upscaling of dendritic spines during sleep. Overall, our findings point to region-and spine type-specific changes in dendritic spines during sleep in the amygdala, which may contribute to consolidation of emotional memories during sleep.

Feasibility, efficacy, and functional relevance of automated auditory closed-loop suppression of slow-wave sleep in humans.

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

SLEEP IS REQUIRED FOR ODOR EXPOSURE TO CONSOLIDATE MEMORY AND REMODEL OLFACTORY SYNAPSES

Abstract Olfactory dysfunction precedes dementia in several neurodegenerative disorders such as Alzheimer’s disease (AD) or Parkinson’s Disease (PD), and AD/PD are associated with progressive sleep abnormalities. However, how sleep affects cognitive performance remains unclear, perhaps due to the complexities of the human nervous system. Here we demonstrate that the transparent model organism C. elegans which has well defined neural connection sleeps after repeated odor trainings. This provides us with a platform to dissect how sleep affects memory at a synaptic resolution. We identified that sleep after training is required for the animal to retain a long-term memory of the odor. We found that if animals do not sleep in the first two hours after training, memory is not consolidated. After identifying the neurons that are required for the memory, we show that the sensory-interneuron connections within the circuit are downscaled after sleep. Therefore, we found a time-specific requirement of sleep that modulates synaptic downscaling to preserve memory. Conversely, lack of sleep post-training erases the long-term memory and destabilizes the synaptic downscaling, indicating that modulating the amount of sleep is sufficient to modulate memory. These results make C. elegans an excellent tool to ask what molecular mechanisms, cell biological processes and circuit level reorganizations are engaged during sleep to promote memory. This understanding will provide insights into the functions of sleep that affects cognitive performance in neurodegenerative diseases.

Acute sleep deprivation induces synaptic remodelling at the soleus muscle neuromuscular junction in rats.

Sleep is important for cognitive and physical performance. Sleep deprivation not only affects neural functions but also results in muscular fatigue. A good night's sleep reverses these functional derangements caused by sleep deprivation. The role of sleep in brain function has been extensively studied. However, its role in neuromuscular junction or skeletal muscle morphology is sparsely addressed although skeletal muscle atonia and suspended thermoregulation during rapid eye movement sleep possibly provide a conducive environment for the muscle to rest and repair; somewhat similar to slow-wave sleep for synaptic downscaling. In the present study, we have investigated the effect of 24h sleep deprivation on the neuromuscular junction morphology and neurochemistry using electron microscopy and immunohistochemistry in the rat soleus muscle. Acute sleep deprivation altered synaptic ultra-structure viz. mitochondria, synaptic vesicle, synaptic proteins, basal lamina, and junctional folds needed for neuromuscular transmission. Further acute sleep deprivation showed the depletion of the neurotransmitter acetylcholine and the overactivity of its degrading enzyme acetylcholine esterase at the neuromuscular junction. The impact of sleep deprivation on synaptic homeostasis in the brain has been extensively reported recently. The present evidence from our studies shows new information on the role of sleep on neuromuscular junction homeostasis and its functioning.

Closed-loop acoustic stimulation during an afternoon nap to modulate subsequent encoding.

Sleep is able to contribute not only to memory consolidation, but also to post-sleep learning. The notion exists that either synaptic downscaling or another process during sleep increase post-sleep learning capacity. A correlation between augmentation of the sleep slow oscillation and hippocampal activation at encoding support the contribution of sleep to encoding of declarative memories. In the present study, the effect of closed-loop acoustic stimulation during an afternoon nap on post-sleep encoding of two verbal (word pairs, verbal learning and memory test) and non-verbal (figural pairs) tasks and on electroencephalogram during sleep and learning were investigated in young healthy adults (N= 16). Closed-loop acoustic stimulation enhanced slow oscillatory and spindle activity, but did not affect encoding at the group level. Subgroup analyses and comparisons with similar studies lead us to the tentative conclusion that further parameters such as time of day and subjects' cognitive ability influenced responses to closed-loop acoustic stimulation.

Sleep homeostasis, seizures, and cognition in children with focalepilepsy.

To investigate the link between sleep disruption and cognitive impairment in childhood epilepsy by studying the effect of epilepsy on sleep homeostasis, as reflected in slow-wave activity (SWA). We examined SWA from overnight EEG-polysomnography in 19 children with focal epilepsy (mean [SD] age 11 years 6 months [3 years], range 6 years 6 months-15 years 6 months; 6 females, 13 males) and 18 age- and sex-matched typically developing controls, correlating this with contemporaneous memory consolidation task scores, full-scale IQ, seizures, and focal interictal discharges. Children with epilepsy did not differ significantly from controls in overnight SWA decline (p=0.12) or gain in memory performance with sleep (p=0.27). SWA was lower in patients compared to controls in the first hour of non-rapid eye movement sleep (p=0.021), although not in those who remained seizure-free (p=0.26). Full-scale IQ did not correlate with measures of SWA in patients or controls. There was no significant difference in SWA measures between focal and non-focal electrodes. Overnight SWA decline is conserved in children with focal epilepsy and may underpin the preservation of sleep-related memory consolidation in this patient group. Reduced early-night SWA may reflect impaired or immature sleep homeostasis in those with a higher seizure burden. The decline in slow-wave activity (SWA) across the night, reflecting global synaptic downscaling, was preserved in children with focal lesional epilepsies. Sleep benefited memory consolidation in this group of patients, as in typically developing children. Reduced early-night SWA was associated with increased likelihood of a subsequent seizure.

0263 Slow-wave Disruption Improves Irritability in Males with Major Depression: Potential Implications for Understanding the Impact of Sex Differences on Sleep and Neuroplasticity

Abstract Introduction Irritability has been proposed to be a core symptom of male-specific major depressive disorder (MDD), with a greater propensity to experiencing anger attacks and overreacting to minor annoyances compared to females with MDD. Males with MDD have also been shown to exhibit a pattern of reduced slow-wave sleep (SWS) that is not characteristic of females. Because SWS has been implicated in the homeostatic regulation of neuroplasticity, it is possible that this mood dysfunction in males is a result of SWS alterations via impairments in neuroplasticity. Therefore, in this study we aimed to manipulate SWS and examine its impact on mood. Methods 19 individuals (11 F) with MDD were recruited for an ongoing clinical trial. Participants spent two nights in the sleep laboratory one week apart: a baseline (BL) night, and a night of slow-wave sleep disruption (SWD) utilizing auditory stimulation. Irritability was assessed in the morning following each overnight visit using the 5-item Brief Irritability Test (BITe). Repeated measures ANOVA was used to evaluate the change in irritability following SWD with condition (BL, SWD) as the within-subject factor and sex (M, F) as the between-subjects factor. Results Results revealed a significant Condition x Sex interaction (F(1,17) =10.1, p=.006) for change in irritability scores, with post-hoc t-tests indicating that males with MDD showed a significant decrease in irritability following SWD, t(7)=2.22, p<.05 while women showed a significant increase in irritability, t(10)=-2.34, p<.05. Changes in irritability were not found to be associated with changes in N3. Conclusion These data demonstrate that experimentally reducing SWS decreases irritability, a core symptom of mood dysfunction, in males with MDD. As SWS has been theorized to facilitate synaptic downscaling, these results may indicate that maintaining waking levels of synaptic strength in males improves depressive symptomatology and may point to the importance of sex differences in sleep and psychopathology. Moreover, these results suggest that the modulation of neuroplasticity via sleep manipulation may be a potential therapeutic target. Support (If Any) K23MH118580 (JG)

Upregulation of IP3 receptor mediates APP-induced defects in synaptic downscaling and sleep homeostasis

Evidence suggests that impaired synaptic and firing homeostasis represents a driving force of early Alzheimer's disease (AD) progression. Here, we examine synaptic and sleep homeostasis in a Drosophila model by overexpressing human amyloid precursor protein (APP), whose duplication and mutations cause familial early-onset AD. We find that APP overexpression induces synaptic hyperexcitability. RNA-seq data indicate exaggerated expression of Ca2+-related signaling genes in APP mutants, including genes encoding Dmca1D, calcineurin (CaN) complex, and IP3R. We further demonstrate that increased CaN activity triggers transcriptional activation of Itpr (IP3R) through activating nuclear factor of activated Tcells (NFAT). Strikingly, APP overexpression causes defects in synaptic downscaling and sleep deprivation-induced sleep rebound, and both defects could be restored by inhibiting IP3R. Our findings uncover IP3R as a shared signaling molecule in synaptic downscaling and sleep homeostasis, and its dysregulation may lead to synaptic hyperexcitability and AD progression at early stage.

Sleep-learning impairs subsequent awake-learning

Although we can learn new information while asleep, we usually cannot consciously remember the sleep-formed memories – presumably because learning occurred in an unconscious state. Here, we ask whether sleep-learning expedites the subsequent awake-learning of the same information. To answer this question, we reanalyzed data (Züst et al., 2019, Curr Biol) from napping participants, who learned new semantic associations between pseudowords and translation-words (guga–ship) while in slow-wave sleep. They retrieved sleep-formed associations unconsciously on an implicit memory test following awakening. Then, participants took five runs of paired-associative learning to probe carry-over effects of sleep-learning on awake-learning. Surprisingly, sleep-learning diminished awake-learning when participants learned semantic associations that were congruent to sleep-learned associations (guga-boat). Yet, learning associations that conflicted with sleep-learned associations (guga-coin) was unimpaired relative to learning new associations (resun-table; baseline). We speculate that the impeded wake-learning originated in a deficient synaptic downscaling and resulting synaptic saturation in neurons that were activated during both sleep-learning and awake-learning.

Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodeling.

Homeostatic scaling in neurons has been attributed to the individual contribution of either translation or degradation; however, there remains limited insight toward understanding how the interplay between the two processes effectuates synaptic homeostasis. Here, we report that a codependence between protein synthesis and degradation mechanisms drives synaptic homeostasis, whereas abrogation of either prevents it. Coordination between the two processes is achieved through the formation of a tripartite complex between translation regulators, the 26S proteasome, and the miRNA-induced silencing complex (miRISC) components such as Argonaute, MOV10, and Trim32 on actively translating transcripts or polysomes. The components of this ternary complex directly interact with each other in an RNA-dependent manner. Disruption of polysomes abolishes this ternary interaction, suggesting that translating RNAs facilitate the combinatorial action of the proteasome and the translational apparatus. We identify that synaptic downscaling involves miRISC remodeling, which entails the mTORC1-dependent translation of Trim32, an E3 ligase, and the subsequent degradation of its target, MOV10 via the phosphorylation of p70 S6 kinase. We find that the E3 ligase Trim32 specifically polyubiquitinates MOV10 for its degradation during synaptic downscaling. MOV10 degradation alone is sufficient to invoke downscaling by enhancing Arc translation through its 3' UTR and causing the subsequent removal of postsynaptic AMPA receptors. Synaptic scaling was occluded when we depleted Trim32 and overexpressed MOV10 in neurons, suggesting that the Trim32-MOV10 axis is necessary for synaptic downscaling. We propose a mechanism that exploits a translation-driven protein degradation paradigm to invoke miRISC remodeling and induce homeostatic scaling during chronic network activity.

Glucocorticoid modulation of synaptic plasticity in the human temporal cortex of epilepsy patients: Does chronic stress contribute to memory impairment?

Memory impairment is common in patients with temporal lobe epilepsy and seriously affects life quality. Chronic stress is a recognized cofactor in epilepsy and can also impair memory function. Furthermore, increased cortisol levels have been reported in epilepsy patients. Animal models have suggested that aggravating effects of stress on memory and synaptic plasticity were mediated via glucocorticoids. The aim of this study was, therefore, to investigate the effect of glucocorticoid receptor (GR) modulation on synaptic plasticity in the human cortex of epilepsy patients. We performed field potential recordings in acute slices from the temporal neocortex of patients who underwent surgery for drug-resistant temporal lobe epilepsy. Synaptic plasticity was investigated by a theta-burst stimulation (TBS) protocol for induction of long-term potentiation (LTP) in the presence of GR modulators. LTP was impaired in temporal cortex from epilepsy patients. Pretreatment of the slices with the GR antagonist mifepristone (RU486) improved LTP induction, suggesting that LTP impairment was due to baseline GR activation in the human cortex. The highly potent GR agonist dexamethasone additionally weakened synaptic strength in an activity-dependent manner when applied after TBS. Our results show a direct negative glucocorticoid effect on synaptic potentiation in the human cortex and imply chronic activation of GRs. Chronic stress may therefore contribute to memory impairment in patients with temporal lobe epilepsy. Furthermore, the activity-dependent acute inhibitory effect of dexamethasone suggests a mechanism of synaptic downscaling by which postictally increased cortisol levels may prevent pathologic plasticity upon seizures.

Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?

Remembering is not a static process: When retrieved, a memory can be destabilized and become prone to modifications. This phenomenon has been demonstrated in a number of brain regions, but the neuronal mechanisms that rule memory destabilization and its boundary conditions remain elusive. Using two distinct computational models that combine Hebbian plasticity and synaptic downscaling, we show that homeostatic plasticity can function as a destabilization mechanism, accounting for behavioral results of protein synthesis inhibition upon reactivation with different re-exposure times. Furthermore, by performing systematic reviews, we identify a series of overlapping molecular mechanisms between memory destabilization and synaptic downscaling, although direct experimental links between both phenomena remain scarce. In light of these results, we propose a theoretical framework where memory destabilization can emerge as an epiphenomenon of homeostatic adaptations prompted by memory retrieval.

Dendritic spine density changes and homeostatic synaptic scaling: a meta-analysis of animal studies.

Mechanisms of homeostatic plasticity promote compensatory changes of cellular excitability in response to chronic changes in the network activity. This type of plasticity is essential for the maintenance of brain circuits and is involved in the regulation of neural regeneration and the progress of neurodegenerative disorders. One of the most studied homeostatic processes is synaptic scaling, where global synaptic adjustments take place to restore the neuronal firing rate to a physiological range by the modulation of synaptic receptors, neurotransmitters, and morphology. However, despite the comprehensive literature on the electrophysiological properties of homeostatic scaling, less is known about the structural adjustments that occur in the synapses and dendritic tree. In this study, we performed a meta-analysis of articles investigating the effects of chronic network excitation (synaptic downscaling) or inhibition (synaptic upscaling) on the dendritic spine density of neurons. Our results indicate that spine density is consistently reduced after protocols that induce synaptic scaling, independent of the intervention type. Then, we discuss the implication of our findings to the current knowledge on the morphological changes induced by homeostatic plasticity.

Learning and memory: Scaling new areas

A new study explores the neural-circuit and synaptic processes that support the transition from general to specific aversive memory formation. A critical role for homeostatic synaptic down-scaling in shaping the specificity of an associative memory is identified.

044 Slow oscillatory transcranial direct current stimulation enhances cognitive performance during subsequent sleep deprivation

Abstract Introduction The EEG slow oscillation of < 1 Hertz frequency has been implicated in various sleep functions, sparking a recent interest in slow oscillation enhancement strategies. In a seminal study, Marshall et al. (2006) demonstrated that 25 minutes of a slow oscillatory form of transcranial direct current stimulation (SO-tDCS) during early nocturnal sleep improved subsequent retention of word pairs learned prior to sleep, consistent with a proposed role for the slow oscillation in sleep-related memory consolidation. Another proposed function of the slow oscillation is synaptic downscaling, hypothesized to constitute the physiological basis for satisfying the homeostatic drive for sleep, per the synaptic homeostasis hypothesis of Tononi and Cirelli. We sought to determine if SO-tDCS could enhance the restorative properties of sleep, by enhancing slow oscillation activity, during a restricted sleep opportunity by assessing performance during a subsequent period of sleep deprivation (SD). Methods Twenty-six healthy volunteers were randomized into two groups. Participants either received electrical stimulation with 50 minutes of SO-tDCS at 0.75Hz, or sham stimulation, during the second hour of a restricted two hour sleep opportunity (11:00PM TO 1:00AM), followed by a 46 hour period of SD and then two recovery nights of sleep. Vigilance was assessed periodically with the Psychomotor Vigilance Test (PVT) during a baseline day, SD, and during the two days following recovery sleep nights. Results A mixed linear regression revealed significant main effects of day, group, and the interaction between group and day on mean reaction time (RT). Posthoc analysis revealed faster RTs following stimulation on day 2 of SD. It was also found that participants in the stimulation group had fewer major lapses (RTs > 500 ms) than those in the sham group over the first three days following stimulation. Conclusion Slow oscillatory transcranial direct current stimulation during a portion of a restricted period of sleep appears to enhance sleep’s restorative properties and improves cognitive performance during subsequent sustained wakefulness. The mechanistic basis for this phenomenon may be increased slow oscillation induced synaptic renormalization. Support (if any) Department of Defense Military Operational Medicine Research Program (MOMRP)