Although sleep is a ubiquitous behavior in animal species with central nervous systems, the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has helped reveal neural pathways in the regulation of sleep/wakefulness. Orexin receptor antagonists, which specifically block the endogenous waking system, have been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.

Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMracG) measurements. We have so far screened >10,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutations in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Indeed, through a systematic cross-comparison of the Sleepy mutants (with a gain-of-function change in a serine/threonine kinase pathway) and sleep-deprived mice, we have found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.

Characteristics of Upper Airway Resistance in Patients with Catathrenia

Xuemei Gao, Yu Min, Zeliang Hao

Stomatology School and Hospital of Peking University

Catathrenia is a rare sleeping disorder, characterized by a prolonged expiration with a monotonous vocalization resembling groaning. Up to 57 Catathrenia patients were investigated with craniofacial morphology, acoustic analyses, masticatory muscle functions, and nasal breathing function, The groaning episode might derive from the partial or intermittent narrowing of the hypopharynx and reactive forced prolonged expiration to overcome this resistance and the active involvement of the vocal cords.

REM sleep is a fundamental sleep state and plays critical roles in a variety of physiological functions. However, the neuronal circuits that regulate REM sleep remain understood. Here, we showed that lateral pontine tegmentum GABAergic (LPT^GABA) neurons were primarily projection to the sublaterodorsal nucleus (SLD). Optogenetic activation of LPTGABA neurons completely terminated REM sleep and promoted REM-to-NREM sleep transitions through SLD and LH pathway. Furthermore, we found that optogenetic activation of RMTg^GABA neurons immediately converted REM sleep to arousal and initiated NREM sleep via LDT and LH pathway, respectively. Taken together, our findings reveal that LPT and RMTg GABAergic neurons are essential for switching off REM sleep and contribute to conversion from REM to NREM sleep.

Insomnia and narcolepsy are common sleep disorders and are difficult to treat, causing heavy burden to patients, families and the society. In clinical practice, insomnia is normally treated with sedatives-hypnotics, and narcolepsy can be treated with stimulants (such as modafinil), selective serotonin reuptake inhibitors, or gamma hydroxybutyric acid (sodium oxybate). However, many of these drugs may have abuse and addiction potential. Here, we will discuss this problem from three aspects: Firstly, we will perform an overview of sedative-hypnotics and arousal-promoting drugs. Secondly, we will discuss the abuse and addiction problem of sedative-hypnotic and arousal-promoting drugs. Thirdly, we will review the regulatory policies of sedative-hypnotics and arousal-promoting drugs, and provide an outlook for their development.

Astrocytes are involved in a number of brain functions, including sleep-awakening regulation. The results show that the active state of astrocytes, such as calcium concentration, is rhythmic in the 24-hour sleep-awakening cycle. The biomarker level of astrocytes in peripheral blood of patients with chronic insomnia changes, which is related to the severity of insomnia. Astrocytes may also be a target for non-invasive neuroregulation such as transcranial electrical stimulation. This article will report on the progress in these areas.