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Physiological rapid eye movement (REM) sleep termination is vital for initiating non-REM (NREM) sleep or arousal, whereas the suppression of excessive REM sleep is promising in treating narcolepsy. However, the neuronal mechanisms controlling REM sleep termination and keeping sleep continuation remain largely unknown. Here, we reveal a key brainstem region of GABAergic neurons in the control of both physiological REM sleep and cataplexy. Using fiber photometry and optic tetrode recording, we characterized the dorsal part of the deep mesencephalic nucleus (dDpMe) GABAergic neurons as REM relatively inactive and two different firing patterns under spontaneous sleep-wake cycles. Next, we investigated the roles of dDpMe GABAergic neuronal circuits in brain state regulation using optogenetics, RNA interference technology, and celltype-specific lesion. Physiologically, dDpMe GABAergic neurons causally suppressed REM sleep and promoted NREM sleep through the sublaterodorsal nucleus and lateral hypothalamus. In-depth studies of neural circuits revealed that sublaterodorsal nucleus glutamatergic neurons were essential for REM sleep termination by dDpMe GABAergic neurons. In addition, dDpMe GABAergic neurons efficiently suppressed cataplexy in a rodent model. Our results demonstrated that dDpMe GABAergic neurons controlled REM sleep termination along with REM/NREM transitions and represented a novel potential target to treat narcolepsy.

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Both human and rodent studies suggest the link between non-rapid eye movement (NREM) sleep and cognition. Recent study indicated that selective activation of cholinergic neurons in basal forebrain inhibits electroencephalogram (EEG) delta power and shortens NREM sleep. In the current study, we aimed to test the pharmacological effect of trihexyphenidyl (THP), a selective muscarinic M1 receptor antagonist, on EEG power spectra and sleep with or without the selective activation of basal forebrain cholinergic neurons. THP (1, 2, and 3 mg/kg) was administrated intraperitoneally in natural sleep phase. Basal forebrain cholinergic neurons expressing modified G protein-coupled muscarinic receptors (hM3Dq) were activated by intraperitoneal injection of clozapine-N-oxide in ChAT-IRES-Cre mice. EEG and electromyogram (EMG) signals were recorded in freely moving mice to analyze EEG power spectrum and sleep hypnogram. Y-maze and novel object recognition tests were used for testing cognition. THP 1 mg/kg significantly increased EEG delta power and facilitated NREM sleep in wildtype mice, while THP 3 mg/kg was required in ChAT-IRES-Cre mice treated with clozapine-N-oxide. THP with dosage up to 8 mg/kg did not induce cognitive impairments in wildtype mice. EEG delta power of NREM sleep is often used as an indicator of sleep depth or sleep quality, which tightly link with sleep-dependent cognition. Taken together, the data collected from rodents hinted that, THP could possibly be used as the NREM sleep facilitator in humans.

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Sexual arousal is an important factor for the success of sexual behavior, and regulated by the central nervous system, its underlying mechanism is very complicated. Androgen is the most important endocrine hormone in men, which is deeply involved in the whole process of male sexual response, but how it regulates male sexual arousal has not been fully clarified and remains one of the hotspots in current andrological research. Therefore, this paper presents an overview of the advances in the studies of the related role and mechanism of androgen in male sexual arousal. In the central nervous system, androgen regulates the release of dopamine neurotransmitters by binding androgen receptors or metabolizing neurosteroids, thus activating the brain reward system. Besides, androgen regulates the neuronal plasticity and spinous process formation in the neural circuit of sexual arousal to ensure successful activation and conduction of the neural circuit. However, the specific regulating mechanism of sexual arousal remains to be further explored.

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Sleep disturbance is generally common in populations as a chronic disease or a complained event. Chronic sleep disturbance is proposed to be closely linked to the pathogenesis of diseases, especially neurodegenerative diseases. We recently found that 2 months of sleep fragmentation initiated Alzheimer's disease (AD)-like behavioral and pathological changes in young wild-type mice. Herein, we present a standardized protocol to achieve chronic sleep fragmentation (CSF). Briefly, CSF was induced by an orbital rotor vibrating at 110 rpm and operating with a repetitive cycle of 10 s-on, 110 s-off, during light-ON phase (8:00 AM-8:00 PM) continuously for up to 2 months. Impairments of spatial learning and memory, anxiety-like but not depression-like behavior in mice as consequences of CSF modeling, were evaluated with Morris water maze (MWM), Novel object recognition (NOR), Open field test (OFT) and Forced swimming test (FST). In comparison with other sleep manipulations, this protocol minimizes the handling labors and maximizes the modeling efficiency. It produces stable phenotypes in young wild-type mice and can be potentially generated for a variety of research purposes.

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AIMS: Insufficient sleep has been found to result in varying degrees of cognitive impairment and emotional changes. Sleep was reported probably responsible for cleaning metabolic wastes in brain by increasing extracellular bulk flow. Herein, we propose that chronic sleep insufficiency in young adult wild-type mice is also linked with dysfunction of intracellular protein degradation pathways and microglia-mediated neuroinflammation, which are potentially important mechanisms in the initiation of neurodegeneration. METHODS: We applied the chronic sleep fragmentation (CSF) model to induce chronic sleep insufficiency in wild-type mice. After 2 months of CSF, cognitive function, amyloid-ß accumulation, dysfunction of endosome-autophagosome-lysosome pathway, and microglia activation were evaluated. RESULTS: Following CSF, impairment of spatial learning and memory, and aggravated anxiety-like behavior in mice were identified by behavioral experiments. Increased intracellular amyloid-ß accumulation was observed in cortex and hippocampus. Mechanistically, CSF could significantly enhance the expression of Rab5 (early endosome marker), Rab7 (late endosome marker), as well as LC3B (autophagosome marker), and autophagy-positive regulatory factors in brain detected by immunofluorescent staining and Western blot. In addition, activation of microglia was evident by enhanced CD68, CD16/32, and CD206 levels after CSF treatment. CONCLUSIONS: Chronic sleep fragmentation could initiate pathogenetic processes similar to the early stage of neurodegeneration, including dysfunction of endosome-autophagosome-lysosome pathway and microglia-mediated neuroinflammation. Our findings further strengthen the link between chronic sleep insufficiency and the initiation of neurodegeneration even if lack of genetic predisposition.

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Autophagy plays vital roles in the pathophysiology of many central nervous system diseases. Emerging evidence indicates that autophagy has both detrimental and protective effects in ischemic cerebral injury. This study aimed to investigate the temporal pattern of autophagy activation in the white matter of bilateral common carotid artery stenosis (BCAS) mouse model by immunofluorescence and western blotting. The effect of wortmannin, an autophagy inhibitor, against hypoperfusion induced white matter injury (WMI) was studied by immunofluorescence and eight-arm radial maze test. We found that autophagy was initially activated in the white matter 3 days after BCAS, and then suppressed by day 10, and was activated again at day 30. Administration of wortmannin during the first three days after BCAS revealed protective effects on axon-glia integrity and against the cognitive injury induced by the chronic hypoperfusion. The results indicated the possible link between autophagy and white matter ischemic damage after chronic cerebral hypoperfusion. Modulation of autophagy in a time course dependent manner may broaden the insight on the treatment of WMI.

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BACKGROUND: Amyloid-ß deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer's disease (AD). Dysregulation of the endosomal-autophagic-lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction. METHODS: We used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4-7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis. To further explore the mechanism of EAL dysregulation in AD, components of the class III phosphatidylinositol 3-kinase (PI3KC3) complex, activators of Rab7 (Beclin1 and UVRAG), and the negative regulator of Rab7 (Rubicon) were also measured in this two brain regions. RESULTS: In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly, EAL pathway, and related PI3KC3 members, UVRAG and Beclin1 were upregulated both in cortex and hippocampus (all P < 0.05). By the age of 12 months old, when abundant amyloid plaques formed, EAL markers, UVRAG, and Beclin1 were also upregulated in the cortex (all P < 0.05). However, Rab7 was decreased significantly (P = 0.0447), accompanied by a reduction of its activating PI3KC complex component Beclin1 (P = 0.0215) and enhancement of its inhibiting component Rubicon (P = 0.0055) in the hippocampus. CONCLUSIONS: Our study implies that EAL pathway, represented as Rab7 and its PI3KC3 regulators' expressions, showed temporal and spatial variation in brains at different stages of AD. It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.

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