Category Archives: Basic Research

Immune Cell Expression of GABAA Receptors and the Effects of Diazepam on Influenza Infection

There is some controversy regarding the effects of using benzodiazepines as sedative agents in critical patients. Previous work has proven that the outcomes are worse as compared to the use of dexmedetomidine regarding length of intubation, length of stay. Other authors have shown an increased incidence of infectious complications, pneumonia, in patients under benzodiazepine sedation. The present paper shows evidence that the expression of GABA A receptors in immune cells is directly related to an increase of duration of influenza infection.

Melatonin is Required for the Circadian Regulation of Sleep

The use of melatonin is controversial as a sleep/circadian rhythm therapeutic. This paper uses the genetic knockout of arylalkylamineN-acetyltransferase 2 (required for melatonin synthesis) in zebrafish to elucidate the role of melatonin in sleep regulation. Zebrafish mutants that lack melatonin have significantly longer latency to sleep and shorter sleep bouts than wild-type fish. In the absence of circadian cues the circadian regulation of sleep is abolished, yet other behavioral and molecular circadian rhythms are maintained. Taken together, these experiments show that melatonin functions downstream of the central circadian pacemakers to promote the timing of and maintenance of sleep in this model system.

Shift Work in Rats Results in Increased Inflammatory Response After Lipopolysaccharide Administration: A Role for Food Consumption

This paper is further evidence that the timing of food around circadian and sleep disruption is relevant to circadian re-entrainment and related processes like inflammation. Using a model of shift work where rats were kept awake for 10 hours during their normal rest period, and then injected with LPS at two time points, the animals that were forced to do “shift work” generated higher levels of inflammation. If food was taken away from the rats during the time of their shift work, the resulting hyper-inflammation was reduced to that of control rats. To further their case, if food was made available only during the normal inactive phase for rats (lights-on period), thus forcing the rats to forage while they may have otherwise been resting caused hyper-inflammation after LPS exposure. These data suggest the importance of the timing of food intake to circadian homeostasis and links circadian disruption, metabolism, and inflammation.

Oxalic Acid and Diacylglycerol 36:3 are Cross-Species Markers of Sleep Debt

This work compares metabolic serum profiles from human subjects and experimental rats subjects to similar sleep restriction protocols. They identified numerous significant changes in lipid metabolism between experimental and control groups in both species. Interestingly amongst all changes, a reduction in the metabolites oxalic acid and diacylglycerol 36:3 strongly correlated with sleep restriction across both species. This work provides an overview of the dysfunctional metabolic profile associated with reduced sleep duration and provides potential biomarkers for sleep loss.

Neuronal Ensembles Sufficient for Recovery Sleep and the Sedative Actions of a2 Adrenergic Agonists

This paper outlines brain regions involved in α-2 adrenergic (α2A) mediated sleep pathways in a mouse model.   By using targeted acute genetic knockdowns of α2A receptors in the locus coeruleus the authors were able to show that the loss of righting reflex and sedation are mediated by α2A agonists but likely involved distinct pathways, and suggesting that LORR is not loss of consciousness but rather a spinal cord inhibitory process. Looking at activated neurons in the hypothalamus they showed a similar pattern of activation between dexmedetomidine-sedated animals and animals in normal recovery sleep.   Targeted reactivation of lateral preoptic neu­rons was sufficient to induce sedation and that GABA inhibition in the same region delayed the sedation caused by dexmedetomidine implying in the involvement of other neuronal subsets in this process.

Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

Patients with Angelman’s syndrome (AS) have imprinting of the paternal allele of the unbiquitin ligase encoded by the Ube3a gene and sleep disturbances inclusive of short sleep duration and increased sleep latency. The authors of this work link Ube3a to modulation of circadian rhythms through the accumulation of the molecular clock protein BMAL1 in a mouse model of AS. AS mice have lengthened endogenous circadian period lengths (which is rescued ex-vivo by unsilencing the paternal allele), and entrain faster to advances in light than wild-type controls. Additionally AS mice have an increased body weight with a higher fat composition than controls. These data provide mechanistic detail to the link between altered metabolism and circadian disruption not only in AS but more broadly as well.

Environmental Disruption of the Circadian Clock Leads to Altered Sleep and Immune Responses in Mouse

Mice chronically maintained on a shortened day schedule (20 hours – 10 hours light : 10 hours dark) as a model of circadian disruption have no total sleep deprivation but lose the nocturnal-diurnal oscillation in REM and NREM percentage present in control animals. When exposed to an in vivo LPS challenge experimental animals demonstrate altered peripheral immune responses notably the chemokine MCP-1, and altered hippocampal cytokine mRNA expression. This work intimates the importance of intact circadian rhythm in generating immune responses and maintaining normal sleep quality.

Differential Acute Effects of Sleep on Spontaneous and Stimulated Production of Tumor Necrosis Factor in Men

This study looked at the effect of sleep deprivation on serum, and released TNF-α from monocytes in human subjects. Sleep deprivation resulted in a blunted oscillation of TNF-α release in-vivo, decreased oscillation of circulating monocytes during the study period and was associated with decreased TNF-α production from LPS stimulated monocytes ex-vivo. Correlation analysis in the normal sleep group points towards a regulatory association of circulating hormones including cortisol, norepinephrine and prolactin. This study is objectively supportive of a widely held belief that normal sleep is necessary for a robust immune response to an innate immune challenge.

Chronic Sleep Fragmentation Induces Endothelial Dysfunction and Structural Vascular Changes in Mice

Long-term sleep fragmentation induces vascular endothelial dysfunction and mild blood pressure increases. Sleep fragmentation also leads to morphologic vessel changes characterized by elastic fiber disruption and disorganization, increased recruitment of inflammatory cells, and altered expression of senescence markers, thereby supporting a role for sleep fragmentation in the cardiovascular morbidity of OSA.