Basic Research Literature Updates

Sleep fragmentation delays wound healing in a mouse model of type 2 diabetes.

The delayed wound healing in obese, diabetic mice caused by SF is homologous to delayed wound healing in some patients with type 2 diabetes. The results support the interpretation that altered leptinergic signaling and inflammatory proteins contribute to delayed wound healing.

Optical probing of orexin/hypocretin receptor antagonists.

The present study investigated the function of Hypocretin (Hcrt or Orexin/OX) receptor antagonists in sleep modulation and memory function with optical methods in transgenic mice. The authors used Hcrt-IRES-Cre knock-in mice and AAV vectors expressing channelrhodopsin-2 (ChR2) to render Hcrt neurons sensitive to blue light stimulation.  Hcrt neurons were optogenetically stimulated and latencies to wakefulness were measured in the presence or absence of OX1/2R antagonists and Zolpidem.

Acute optogenetic stimulation of Hcrt neurons at different frequencies resulted in wakefulness. Treatment with dual OX1/2R antagonists (DORAs) DORA12 and MK6096, as well as selective OX2R antagonist MK1064 and Zolpidem, but not selective OX1R antagonist 1SORA1, significantly reduced the bout length of optogenetic stimulation-evoked wakefulness episode. DORAs and selective OX2R antagonists stabilize sleep and improve sleep-dependent cognitive processes even when challenged by optogenetic stimulation mimicking highly arousing stimuli.

Connectivity of sleep- and wake-promoting regions of the human hypothalamus observed during resting wakefulness

The findings of this study provide preliminary evidence relating a hypothalamic circuit investigated in animals to sleep–wake neuroimaging results in humans, with implications for our understanding of human sleep–wake regulation and the functional significance of anticorrelations.

Sleep-disordered breathing in C57BL/6J mice with diet-induced obesity

Obesity leads to sleep-disordered breathing (SDB) manifested by recurrent upper airway obstructions termed obstructive sleep apnea (OSA) and carbon dioxide retention due to hypoventilation. The objective of this work was to characterize breathing during sleep in C57BL6/J mice with diet-induced obesity (DIO). (…) We conclude that DIO in mice leads to hypoventilation. Obesity also increases the frequency of inspiratory limited breaths, but it does not translate into progression of OSA.

Acute Kynurenine Challenge Disrupts Sleep-Wake Architecture and Impairs Contextual Memory in Adult Rats

Tryptophan metabolism via the kynurenine pathway may represent a key molecular link between sleep loss and cognitive dysfunction.

The results of this study  introduce kynurenine pathway metabolism and formation of metabolite kynurenic acid  as a novel molecular target contributing to sleep disruptions and cognitive impairments.

Effects of Optogenetic inhibition of BLA on Sleep Brief Optogenetic Inhibition of the Basolateral Amygdala in Mice Alters Effects of Stressful Experiences on Rapid Eye Movement Sleep

Authors: Machida M, Wellman LL, Fitzpatrick Bs ME, Hallum Bs O, Sutton Bs AM, Lonart G, Sanford LD.

Glutamatergic cells in BLA can modulate the effects of stress on REM and can mediate effects of fear memory on sleep that can be independent of behavioral fear.”

Circadian Gene Variants Influence Sleep and the Sleep Electroencephalogram in Humans

The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25-1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75-4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep.

Changes in the Composition of Brain Interstitial Ions Control the Sleep-Wake Cycle

Wakefulness is driven by the widespread release of neuromodulators by the ascending arousal system. Yet, it is unclear how these substances orchestrate state-dependent, global changes in neuronal activity. Here, we show that neuromodulators induce increases in the extracellular K(+) concentration ([K(+)]e) in cortical slices electrically silenced by tetrodotoxin. In vivo, arousal was linked to AMPA receptor-independent elevations of [K(+)]e concomitant with decreases in [Ca(2+)]e, [Mg(2+)]e, [H(+)]e, and the extracellular volume. Opposite, natural sleep and anesthesia reduced [K(+)]e while increasing [Ca(2+)]e, [Mg(2+)]e, and [H(+)]e as well as the extracellular volume. Local cortical activity of sleeping mice could be readily converted to the stereotypical electroencephalography pattern of wakefulness by simply imposing a change in the extracellular ion composition. Thus, extracellular ions control the state-dependent patterns of neural activity.

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

This work delineates the normal oscillation and responsiveness of circulating monocytes and T lymphocytes in ten human volunteers over circadian time. Under normal circadian parameters, bimodal cytokine secretion was observed with the night peak caused by an increased responsiveness of monocytes, and the day peak corresponding to a higher absolute number of monocytes. T lymphocytes demonstrated an evening peak caused by both higher cell count and responsiveness. When subjected to a night shift schedule (acute circadian disruption) monocyte and T cells circulating phase was not changed but the responsiveness of both cell types was advanced (earlier expression of cytokine) after stimulation. This suggests that acute changes in sleep-wake cycles alter the cell intrinsic responsiveness to stimulation whereas parameters governing circulation may lag behind.

Chronic Intermittent Hypoxia Alters Local Respiratory Circuit Function at the Level of the preBötzinger Complex

The preBotzinger complex in rats is a respiratory neuronal network driving inspiratory rhythm. Chronic intermittent hypoxia (as is the case in OSA) causes irregular firing of the preBotzinger complex. Dysrhythmia in the preBotzinger complex loosens the coupling of neuronal transmission with XIIn. Lipid peroxidation is increased in both the preBotzinger complex and XIIn as a result of chronic intermittent hypoxia. Treatment with antioxidant can reverse the instability in neuronal coupling caused by the exposure hypoxia. This work demonstrates the effect of hypoxia on rhythmic breathing in a salient neuronal network and provides a possible therapeutic strategy to re-establish rhythmic neuronal connectivity in this pathway.