Recovering object-location memories after sleep deprivation-induced amnesia.

It is well established that sleep deprivation after learning impairs hippocampal memory processes and can cause amnesia. It is unknown, however, whether sleep deprivation leads to the loss of information or merely the suboptimal storage of information that is difficult to retrieve. Here, we show that hippocampal object-location memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training, using optogenetic dentate gyrus (DG) memory engram activation or treatment with the clinically approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, the combination of optogenetic DG memory engram activation and roflumilast treatment, 2 days following training and sleep deprivation, made the memory more persistently accessible for retrieval even several days later (i.e., without further optogenetic or pharmacological manipulation). Altogether, our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss but instead leads to the suboptimal storage of information that cannot be retrieved without drug treatment or optogenetic stimulation. Furthermore, our findings suggest that object-location memories, consolidated under sleep deprivation conditions and thought to be lost, can be made accessible again several days after the learning and sleep deprivation episode, using the clinically approved PDE4 inhibitor roflumilast.

Sleep deprivation reduces the density of individual spine subtypes in a branch-specific fashion in CA1 neurons.

Sleep deprivation has a negative impact on hippocampus-dependent memory, which is thought to depend on cellular plasticity. We previously found that 5 h of sleep deprivation robustly decreases dendritic spine density in the CA1 area of the hippocampus in adult male mice. However, recent work by others suggests that sleep deprivation increases the density of certain spine types on specific dendritic branches. Based on these recent findings and our previous work, we conducted a more in-depth analysis of different spine types on branches 1, 2 and 5 of both apical and basal dendrites to assess whether 5 h of sleep deprivation may have previously unrecognized spine-type and branch-specific effects. This analysis shows no spine-type specific changes on branch 1 and 2 of apical dendrites after sleep deprivation. In contrast, sleep deprivation decreases the number of mushroom and branched spines on branch 5. Likewise, sleep deprivation reduces thin, mushroom and filopodia spine density on branch 5 of the basal dendrites, without affecting spines on branch 1 and 2. Our findings indicate that sleep deprivation leads to local branch-specific reduction in the density of individual spine types, and that local effects might not reflect the overall impact of sleep deprivation on CA1 structural plasticity. Moreover, our analysis underscores that focusing on a subset of dendritic branches may lead to potential misinterpretation of the overall impact of, in this case, sleep deprivation on structural plasticity.

The role of clock genes in sleep, stress and memory.

Circadian clock genes serve as the molecular basis for animals' ~24-h internal timekeeping. Clock gene expression inside and outside of the mammalian brain's circadian pacemaker (i.e. the SCN) integrates temporal information into a wealth of physiological processes. Ample data suggests that in addition to canonical cellular timekeeping functions, clock proteins also interact with proteins involved in cellular processes not related to timekeeping, including protein regulation and the interaction with other signaling mechanisms not directly linked to the regulation of circadian rhythms. Indeed, recent data suggests that clock genes outside the SCN are involved in fundamental brain processes such as sleep/wakefulness, stress and memory. The role of clock genes in these brain processes are complex and divers, influencing many molecular pathways and phenotypes. In this review, we will discuss recent work on the involvement of clock genes in sleep, stress, and memory. Moreover, we raise the controversial possibility that these functions may be under certain circumstances independent of their circadian timekeeping function.

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.

Noradrenergic enhancement of object recognition and object location memory in mice.

Extensive evidence indicates that noradrenergic activation is essentially involved in mediating the enhancing effects of emotional arousal on memory consolidation. Our current understanding of the neurobiological mechanisms underlying the memory-modulatory effects of the noradrenergic system is primarily based on pharmacological studies in rats, employing targeted administration of noradrenergic drugs into specific brain regions. However, the further delineation of the specific neural circuitry involved would benefit from experimental tools that are currently more readily available in mice. Previous studies have not, as yet, investigated the effect of noradrenergic enhancement of memory in mice, which show different cognitive abilities and higher endogenous arousal levels induced by a training experience compared to rats. In the present study, we investigated the effect of posttraining noradrenergic activation in male C57BL/6J mice on the consolidation of object recognition and object location memory. We found that the noradrenergic stimulant yohimbine (0.3 or 1.0 mg/kg) administered systemically immediately after an object training experience dose-dependently enhanced 24-h memory of both the identity and location of the object. Thus, these findings indicate that noradrenergic activation also enhances memory consolidation processes in mice, paving the way for a systematic investigation of the neural circuitry underlying these emotional arousal effects on memory.LAY SUMMARY: The current study successfully validated the effect of noradrenergic activation on both object recognition and object location memory in mice. This study thereby provides a fundamental proof-of-principle for the investigation of the neural circuitry underlying noradrenergic and arousal effects on long-term memory in mice.

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.

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.