Molecular Biology and Genetics

Injection of nanomolar amounts of prostaglandin D 2 (PGD 2) into the rat brain has dose and time-dependent somnogenic effects, and the PGD 2-induced sleep is indistinguishable from physiologic sleep. Sleep-inducing PGD 2 is produced in the brain by lipocalin-type PGD 2 synthase (LPGDS). Three potential intracranial sources of LPGDS have been identified: oligodendrocytes, choroid plexus, and leptomeninges. We aimed at the identification of the site of synthesis of somnogenic PGD 2 and therefore, generated a transgenic mouse line with the LPGDS gene amenable to conditional deletion using Cre recombinase (flox-LPGDS mouse). To identify the cell type responsible for producing somnogenic PGD 2 , we engineered animals lacking LPGDS expression specifically in oligodendrocytes (OD-LPGDS KO), choroid plexus (CP-LPGDS KO), or leptomeninges (LM-LPGDS KO). We measured prostaglandins and LPGDS concentrations together with PGD synthase activity in the brain of these mice. While the LPGDS amount and PGD synthase activity were drastically reduced in the ODand LM-LPGDS KO mice, they were unchanged in the CP-LPGDS KO mice compared with control animals. We then recorded electroencephalograms, electromyograms, and locomotor activity to measure sleep in 10-week-old mice with specific knockdown of LPGDS in each of the three targets. Using selenium tetrachloride, a specific PGDS inhibitor, we demonstrated that sleep is inhibited in OD-LPGDS and CP-LPGDS KO mice, but not in the LM-LPGDS KO mice. We concluded that somnogenic PGD 2 is produced primarily by the leptomeninges, and not by oligodendrocytes or choroid plexus.

Social conflict is a major source of stress in humans. Animals also experience social conflicts and cope with them by stress responses that facilitate arousal and activate sympathetic and neuroendocrine systems. The effect of acute social defeat (SoD) stress on the sleep/wake behavior of mice has been reported in several models based on a resident-intruder paradigm. However, the post-SoD stress sleep/wake effects vary between the studies and the contribution of specific effects in response to SoD or nonspecific effects of the SoD procedure (e.g., sleep deprivation) is not well established. In this study, we established a mouse model of acute SoD stress based on strong aggressive mouse behavior toward unfamiliar intruders. In our model, we prevented severe attacks of resident mice on submissive intruder mice to minimize behavioral variations during SoD. In response to SoD, slow-wave sleep (SWS) strongly increased during 9 h. Although some sleep changes after SoD stress can be attributed to nonspecific effects of the SoD procedure, most of the SWS increase is likely a specific response to SoD. Slow-wave activity was only enhanced for a short period after SoD and dissipated long before the SWS returned to baseline. Moreover, SoD evoked a strong corticosterone response that may indicate a high stress level in the intruder mice after SoD. Our SoD model may be useful for studying the mechanisms and functions of sleep in response to social stress.

and SWS circadian modulation of GFS was not observed but prominent sleep-dependent reduction was observed across all studied frequency bands except the theta (4.5e7.5 Hz) and the sigma (11e15 Hz) bands, respectively. Conclusions: These data demonstrate that the global brain neural connectivity as measured by GFS is modulated by circadian rhythmicity and sleep history in a frequency and vigilance state dependent manner with some differences between men and women.

The therapeutic potential of targeting adenosine A2A receptors (A2ARs) is immense due to their broad expression in the body and central nervous system. The role of A2ARs in cardiovascular function, inflammation, sleep/wake behaviors, cognition, and other primary nervous system functions has been extensively studied. Numerous A2AR agonist and antagonist molecules are reported, many of which are currently in clinical trials or have already been approved for treatment. Allosteric modulators can selectively elicit a physiologic response only where and when the orthosteric ligand is released, which reduces the risk of an adverse effect resulting from A2AR activation. Thus, these allosteric modulators have a potential therapeutic advantage over classical agonist and antagonist molecules. This review focuses on the recent developments regarding allosteric A2AR modulation, which is a promising area for future pharmaceutical research because the list of existing allosteric A2AR modulators an...

Introduction: Insomnia is one of the most common sleep problems with an estimated prevalence of 10-15% in the general population and 30-60% in the older population. The adenosine A2A receptor (A2AR) agonist CGS 21680 induces sleep when infused into the brain of rodents. However, it is commonly believed that administration of an A2AR agonist has limited clinical potential for treating sleep disorders, because of its cardiovascular side effects, including hypotension and tachycardia. Moreover, all currently existing A2AR agonists are not suitable for treating the central nervous system due to the lack of brain permeability, as it is widely accepted