Intracerebral adenosine during sleep deprivation : A meta-analysis and new experimental data

Funding Information: The systematic review was funded by The Netherlands Organisation for Health Research and Development (ZonMW; 114024101); R2N, Federal State of Lower Saxony; and the DFG (FOR2591, BL 953/11-1). The microdialysis experiment was funded by Netherlands Organization for Scientific Research (NWO; 051-04-010, to Eus van Some-ren). The HPLC adenosine measurements were funded by the University of Helsinki sleep team and a travel grant from the European Sleep Research Society. Publisher Copyright: © 2018 Ubiquity Press. All rights reserved.The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of washout, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted.Peer reviewe

Individual differences in dopamine efflux in nucleus accumbens shell and core during instrumental learning

Combined activation of dopamine D1- and NMDA-glutamate receptors in the nucleus accumbens has been strongly implicated in instrumental learning, the process in which an individual learns that a specific action has a wanted outcome. To assess dopaminergic activity, we presented rats with two sessions (30 trials each) of a one-lever appetitive instrumental task and simultaneously measured dopamine efflux in the shell and core accumbens subareas using in vivo microdialysis. Dopamine efflux was increased during each session in all areas. The behavioral performance of the rats in the second session led us to divide them into a learning group (>90% correct trials) and a nonlearning group. In the first session, the rats of the learning group showed significantly higher increases. The difference was most pronounced in the shell. In the second session, the dopamine increase was similar in both groups, although the learning groups now pressed the lever about three times more often and consequently obtained more rewards. We conclude that task-related activation of dopamine efflux is different between learning and nonlearning rats only during the learning phase. These results support the pharmacological evidence that dopamine is of particular importance during the instrumental learning process

Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at β receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory discrimination. They were injected with a β adrenergic receptor antagonist into the PL 5 min or 2 h after training and tested 48 h later. Rats injected at 2 h showed amnesia, whereas those injected at 5 min had good retention, equivalent to saline-injected controls. Monitoring extracellular noradrenaline efflux in PL by in vivo microdialysis during the first hours after training revealed a significant increase shortly after training, with a rapid return to baseline, and then another increase around the 2-h posttraining time window. Pseudo-trained rats showed a smaller early efflux and did not show the second wave of efflux at 2 h. These results confirm earlier pharmacological and immunohistochemical studies suggesting a delayed role of noradrenaline in a late phase of long-term memory consolidation and the engagement of the PL during these consolidation processes

Intracerebral adenosine during sleep deprivation : A meta-analysis and new experimental data

Funding Information: The systematic review was funded by The Netherlands Organisation for Health Research and Development (ZonMW; 114024101); R2N, Federal State of Lower Saxony; and the DFG (FOR2591, BL 953/11-1). The microdialysis experiment was funded by Netherlands Organization for Scientific Research (NWO; 051-04-010, to Eus van Some-ren). The HPLC adenosine measurements were funded by the University of Helsinki sleep team and a travel grant from the European Sleep Research Society. Publisher Copyright: © 2018 Ubiquity Press. All rights reserved.The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of washout, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted.Peer reviewe

Spatial reversal learning is robust to total sleep deprivation

Sleep deprivation affects cognitive functions that depend on the prefrontal cortex (PFC) such as cognitive flexibility, and the consolidation of newly learned information. The identification of cognitive processes that are either robustly sensitive or robustly insensitive to the same experimental sleep deprivation procedure, will allow us to better focus on the specific effects of sleep on cognition, and increase understanding of the mechanisms involved. In the present study we investigate whether sleep deprivation differentially affects the two separate cognitive processes of acquisition and consolidation of a spatial reversal task.After training on a spatial discrimination between two levers in a Skinner box, male Wistar rats were exposed to a reversal of the previously learned stimulus-response contingency. We first evaluated the effect of sleep deprivation on the acquisition of reversal learning. Performance on reversal learning after 12. h of sleep deprivation (n=12) was compared to performance after control conditions (n=12). The second experiment evaluated the effect of sleep deprivation on the consolidation of reversal learning; the first session of reversal learning was followed by 3. h of nap prevention (n=8) or undisturbed control conditions (n=8). The experiments had sufficient statistical power (0.90 and 0.81, respectively) to detect differences with medium effect sizes.Neither the acquisition, nor the consolidation, of reversal learning was affected by acute sleep deprivation. Together with previous findings, these results help to further delineate the role of sleep in cognitive processing

Risk-Based Decision Making: A Systematic Scoping Review of Animal Models and a Pilot Study on the Effects of Sleep Deprivation in Rats

Animals, including humans, frequently make decisions involving risk or uncertainty. Different strategies in these decisions can be advantageous depending the circumstances. Short sleep duration seems to be associated with more risky decisions in humans. Animal models for risk-based decision making can increase mechanistic understanding, but very little data is available concerning the effects of sleep. We combined primary- and meta-research to explore the relationship between sleep and risk-based decision making in animals. Our first objective was to create an overview of the available animal models for risky decision making. We performed a systematic scoping review. Our searches in Pubmed and Psychinfo retrieved 712 references, of which 235 were included. Animal models for risk-based decision making have been described for rodents, non-human primates, birds, pigs and honey-bees. We discuss task designs and model validity. Our second objective was to apply this knowledge and perform a pilot study on the effect of sleep deprivation. We trained and tested male Wistar rats on a probability discounting task; a “safe” lever always resulted in 1 reward, a “risky” lever resulted in 4 or no rewards. Rats adapted their preferences to variations in reward probabilities (p < 0.001), but 12 h of sleep deprivation during the light phase did not clearly alter risk preference (p = 0.21)

Intermediate filament transcription in astrocytes is repressed by proteasome inhibition

Increased expression of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) is a characteristic of astrogliosis. This process occurs in the brain during aging and neurodegeneration and coincides with impairment of the ubiquitin proteasome system. Inhibition of the proteasome impairs protein degradation; therefore, we hypothesized that the increase in GFAP may be the result of impaired proteasomal activity in astrocytes. We investigated the effect of proteasome inhibitors on GFAP expression and other intermediate filament proteins in human astrocytoma cells and in a rat brain model for astrogliosis. Extensive quantitative RT-PCR, immunocytochemistry, and Western blot analysis resulted unexpectedly in a strong decrease of GFAP mRNA to <4% of control levels [Control (DMSO) 100±19.2%; proteasome inhibitor (epoxomicin) 3.5±1.3%, n=8; P≤0.001] and a loss of GFAP protein in astrocytes in vitro. We show that the proteasome alters GFAP promoter activity, possibly mediated by transcription factors as demonstrated by a GFAP promoter-luciferase assay and RT(2) Profiler PCR array for human transcription factors. Most important, we demonstrate that proteasome inhibitors also reduce GFAP and vimentin expression in a rat model for induced astrogliosis in vivo. Therefore, proteasome inhibitors could serve as a potential therapy to modulate astrogliosis associated with CNS injuries and disease.—Middeldorp, J., Kamphuis, W., Sluijs, J. A., Achoui, D., Leenaars, C. H. C., Feenstra, M. G. P., van Tijn, P., Fischer, D. F., Berkers, C., Ovaa, H., Quinlan, R. A., Hol, E. M. Intermediate filament transcription in astrocytes is repressed by proteasome inhibition

Risk-Based Decision Making: A Systematic Scoping Review of Animal Models and a Pilot Study on the Effects of Sleep Deprivation in Rats

Animals, including humans, frequently make decisions involving risk or uncertainty. Different strategies in these decisions can be advantageous depending the circumstances. Short sleep duration seems to be associated with more risky decisions in humans. Animal models for risk-based decision making can increase mechanistic understanding, but very little data is available concerning the effects of sleep. We combined primary- and meta-research to explore the relationship between sleep and risk-based decision making in animals. Our first objective was to create an overview of the available animal models for risky decision making. We performed a systematic scoping review. Our searches in Pubmed and Psychinfo retrieved 712 references, of which 235 were included. Animal models for risk-based decision making have been described for rodents, non-human primates, birds, pigs and honey-bees. We discuss task designs and model validity. Our second objective was to apply this knowledge and perform a pilot study on the effect of sleep deprivation. We trained and tested male Wistar rats on a probability discounting task; a “safe” lever always resulted in 1 reward, a “risky” lever resulted in 4 or no rewards. Rats adapted their preferences to variations in reward probabilities (p < 0.001), but 12 h of sleep deprivation during the light phase did not clearly alter risk preference (p = 0.21)