Sleep as a synaptic architect:How sleep loss influences memory and synaptic plasticity

Due to the increasing economic and social pressure to be available outside normal working hours, many people do not get enough sleep. One of the negative consequences of sleep deprivation is impaired memory formation. Memories are formed using a structure located in the temporal lobe of the brain called the hippocampus. Even a single night of sleep deprivation can cause memory problems, which is reflected by a loss of connections between brain cells (neurons), within the hippocampus. The aim of this project was to investigate how hippocampus-dependent memory formation is influenced by sleep deprivation and day-night rhythm. For this purpose, we used mice as a model, as the structure of the human hippocampus is comparable to the one of mice, and because they go through the same sleep phases (REM, non-REM sleep).The results from this thesis suggest that the effects of sleep deprivation on the neuronal connections can differ per brain area, and may even differ in one particular brain structure, such as the hippocampus. We also showed that memory problems after sleep deprivation are not mediated by stress hormones. Furthermore, these data indicate that the formation of new proteins plays an important role for memory storage immediately after a learning task up to 8 hours later, irrespective of timing of training. Understanding how sleep deprivation causes memory problems will hopefully lead to more awareness of the biological necessity of sleep and the importance of allowing enough time for it in this modern society

A brief period of sleep deprivation leads to subtle changes in mouse gut microbiota

Not getting enough sleep is a common problem in our society and contributes to numerous health problems, including high blood pressure, diabetes and obesity. Related to these observations, a wealth of studies has underscored the negative impact of both acute and chronic sleep deprivation on cognitive function. More recently it has become apparent that the gut microbiota composition can be rapidly altered, modulates brain function and is affected by the aforementioned health problems. As such, changes in the microbiota composition may contribute to the behavioural and physiological phenotypes associated with sleep deprivation. It is unclear, however, whether a brief period of sleep deprivation can also negatively impact the gut microbiota. Here, we examined the impact of 5 hr of sleep deprivation on gut microbiota composition of male C57Bl6/J mice. Despite the fact that the overall microbial composition did not change between the control- and sleep-deprived groups, the relative abundance of the Clostridiaceae and Lachnospiraceae were slightly altered in sleep-deprived animals compared to controls. Together, these data suggest that depriving mice of sleep for 5 hr leads to subtle changes in the gut microbiota composition

Sleep deprivation-induced impairment of memory consolidation is not mediated by glucocorticoid stress hormones

The general consensus is that sleep promotes neuronal recovery and plasticity, whereas sleep deprivation (SD) impairs brain function, including cognitive processes. Indeed, a wealth of data has shown a negative impact of SD on learning and memory processes, particularly those that involve the hippocampus. The mechanisms underlying these negative effects of sleep loss are only partly understood, but a reoccurring question is whether they are in part caused by stress hormones that may be released during SD. The purpose of the present study is therefore to examine the role of glucocorticoid stress hormones in SD-induced memory impairment. Male C57BL/6J mice were trained in an object-location memory paradigm, followed by 6 hr of SD by mild stimulation. At the beginning of the SD mice were injected with the corticosterone synthesis inhibitor metyrapone. Memory was tested 24 hr after training. Blood samples taken in a separate group of mice showed that SD resulted in a mild but significant increase in plasma corticosterone levels, which was prevented by metyrapone. However, the SD-induced impairment in object-location memory was not prevented by metyrapone treatment. This indicates that glucocorticoids play no role in causing the memory impairments seen after a short period of SD

Modal Analysis of Harmonically Forced Turbulent Flows with Application to Jets

Many turbulent flows exhibit time-periodic statistics. These include flows in turbomachinery, the wakes of bluff bodies, and flows exposed to harmonic actuation. However, many existing techniques for identifying and modeling coherent structures, most notably spectral proper orthogonal decomposition (SPOD) and resolvent analysis, assume statistical stationarity. In this thesis, we develop extensions to study turbulent flows with periodic statistics. We focus on the application of turbulent jets and jet noise reduction through harmonic actuation, which is of interest for both commercial and military aviation due to its success in reducing noise by up to 5dB. To analyze the coherent structures in harmonically forced flows, we develop the cyclostationary spectral proper orthogonal decomposition (CS-SPOD). We examine the resulting properties of CS-SPOD and develop a theoretical connection between CS-SPOD and harmonic resolvent analysis (HRA), thereby providing the theoretical basis for HRA to be used as a model for coherent structures of cyclostationary flows. We develop and validate a computationally efficient algorithm and then illustrate its efficacy using the linearized (complex) Ginzburg-Landau equation. We next employ cyclostationary analysis to investigate the impact of an axisymmetric acoustic harmonic forcing on the mean, turbulence, and coherent structures of a round turbulent jet with a Mach number of 0.4 and a Reynolds number of 450000. We perform large-eddy simulations for four cases at two forcing frequencies and amplitudes. Both low-frequency (Strouhal number of 0.3) and high-frequency (Strouhal number of 1.5) forcing is found to generate an energetic, nonlinear, tonal response consisting of the rollup of vortices via the Kelvin-Helmholtz mechanism. However, the impact of forcing on the broadband turbulence and coherent structures is limited, particularly at the low forcing amplitude associated with jet-noise-reduction devices. Additionally, the dominant coherent structures for the forced jets are similar in their energy, structure, and mechanism. At high forcing amplitudes, phase-dependent features arise in the dominant coherent structures and are associated with coupling to the high-velocity/shear regions of the mean. Overall, our results support the existing hypotheses that jet noise reduction can be associated with the deformation of the mean flow field rather than through direct interaction between the forcing and the turbulence. Lastly, we find that HRA predicts the dominant coherent structures well. This shows that HRA can be used to develop models of forced jets in a similar manner to how resolvent is employed for natural jets, which may be useful to guide future sound-source models of jets subjected to active control.</p

Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation

Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep

Elucidating the role of protein synthesis in hippocampus-dependent memory consolidation across the day and night

It is widely acknowledged that de novo protein synthesis is crucial for the formation and consolidation of long‐term memories. While the basal activity of many signaling cascades that modulate protein synthesis fluctuates in a circadian fashion, it is unclear whether the temporal dynamics of protein synthesis‐dependent memory consolidation vary depending on the time of day. More specifically, it is unclear whether protein synthesis inhibition affects hippocampus‐dependent memory consolidation in rodents differentially across the day (i.e., the inactive phase with an abundance of sleep) and night (i.e., the active phase with little sleep). To address this question, male and female C57Bl6/J mice were trained in a contextual fear conditioning task at the beginning or the end of the light phase. Animals received a single systemic injection with the protein synthesis inhibitor anisomycin or vehicle directly, 4, 8 hr, or 11.5 hr following training, and memory was assessed after 24 hr. Here, we show that protein synthesis inhibition impaired the consolidation of context–fear memories selectively when the protein synthesis inhibitor was administered at the first three time points, irrespective of timing of training. Even though the basal activity of signaling pathways regulating de novo protein synthesis may fluctuate across the 24‐hr cycle, these results suggest that the temporal dynamics of protein synthesis‐dependent memory consolidation are similar for day‐time and night‐time learning

Cofilin overactivation improves hippocampus-dependent short-term memory

Many living organisms of the animal kingdom have the fundamental ability to form and retrieve memories. Most information is initially stored as short-term memory, which is then converted to a more stable long-term memory through a process called memory consolidation. At the neuronal level, synaptic plasticity is crucial for memory storage. It includes the formation of new spines, as well as the modification of existing spines, thereby tuning and shaping synaptic efficacy. Cofilin critically contributes to memory processes as upon activation, it regulates the shape of dendritic spines by targeting actin filaments. We previously found that prolonged activation of cofilin in hippocampal neurons attenuated the formation of long-term object-location memories. Because the modification of spine shape and structure is also essential for short-term memory formation, we determined whether overactivation of hippocampal cofilin also influences the formation of short-term memories. To this end, mice were either injected with an adeno-associated virus expressing catalytically active cofilin, or an eGFP control, in the hippocampus. We show for the first time that cofilin overactivation improves short-term memory formation in the object-location memory task, without affecting anxiety-like behavior. Surprisingly, we found no effect of cofilin overactivation on AMPA receptor expression levels. Altogether, while cofilin overactivation might negatively impact the formation of long-lasting memories, it may benefit short-term plasticity.</p