Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep

• Published in: Nature (London) 2017-08, Vol.548 (7669), p.582-587
• Main Authors: Liu, Kai, Kim, Juhyun, Kim, Dong Won, Zhang, Yi Stephanie, Bao, Hechen, Denaxa, Myrto, Lim, Szu-Aun, Kim, Eileen, Liu, Chang, Wickersham, Ian R., Pachnis, Vassilis, Hattar, Samer, Song, Juan, Brown, Solange P., Blackshaw, Seth
• Format: Article
• Language: English
• Subjects: 13; 14/19; 38/1; 38/32; 38/35; 42; 42/41; 42/44; 59; 631/378/1385/2641; 631/378/1385/2643; 631/378/1385/519; 631/378/2571/2578; 64; 64/60; 9/74; 96/44; Animals; Cell Lineage; Clonal deletion; Diencephalon; Eye movements; GABA; GABAergic Neurons - drug effects; GABAergic Neurons - metabolism; GABAergic Neurons - secretion; gamma-Aminobutyric Acid - secretion; Gene Deletion; Gene expression; Health aspects; Hippocampus - cytology; Hippocampus - physiology; Homeobox; Humanities and Social Sciences; Hypothalamus; Hypothalamus (lateral); letter; LIM-Homeodomain Proteins - deficiency; LIM-Homeodomain Proteins - drug effects; LIM-Homeodomain Proteins - genetics; LIM-Homeodomain Proteins - metabolism; Male; Mice; multidisciplinary; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - drug effects; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Neurotransmitters; NREM sleep; Orexins; Orexins - metabolism; Physiological aspects; Presynaptic Terminals - metabolism; REM sleep; Science; Sleep; Sleep - drug effects; Sleep - genetics; Sleep - physiology; Sleep and wakefulness; Sleep, REM - drug effects; Sleep, REM - genetics; Sleep, REM - physiology; Time Factors; Transcription Factors - deficiency; Transcription Factors - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Wakefulness; Wakefulness - drug effects; Wakefulness - genetics; Wakefulness - physiology; Zona incerta; Zona Incerta - cytology; Zona Incerta - drug effects; Zona Incerta - physiology; γ-Aminobutyric acid
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature23663

GABAergic Lhx6 + neurons in the ventral zona incerta promote both rapid eye movement and non-rapid eye movement sleep and inhibit the activity of wake-promoting GABAergic and Hcrt + neurons of the lateral hypothalamus. Sleep-inducing neurons Various populations of neurons that can promote wakefulness have been identified, but only a small number of neuronal populations that promote sleep have been described. Here, Seth Blackshaw and colleagues reveal that specific inhibitory neurons in the zona incerta become more active as sleep need increases, inhibiting the activity of wake-promoting neurons in the lateral hypothalamus. Midbrain deletion of Lhx6, a transcription factor that defines these inhibitory zona incerta neurons, can lead to decreases in both NREM and REM sleep. Further exploration of the gene expression networks that drive the development and function of these Lhx6-expressing neurons may identify other factors that are critical to sleep regulation. Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified 1 . Wake-promoting cell types include hypocretin and GABA (γ-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep 2 , 3 . Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep–wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep.