25 results found
Tossell K, Yu X, Soto BA, et al., 2020, Sleep deprivation triggers somatostatin neurons in prefrontal cortex to initiate nesting and sleep via the preoptic and lateral hypothalamus, Publisher: bioRxiv
Animals undertake specific behaviors before sleep. Little is known about whether these innate behaviors, such as nest building, are actually an intrinsic part of the sleep-inducing circuitry. We found, using activity-tagging genetics, that mouse prefrontal cortex (PFC) somatostatin/GABAergic (SOM/GABA) neurons, which become activated during sleep deprivation, induce nest building when opto-activated. These tagged neurons induce sustained global NREM sleep if their activation is prolonged metabotropically. Sleep-deprivation-tagged PFC SOM/GABA neurons have long-range projections to the lateral preoptic (LPO) and lateral hypothalamus (LH). Local activation of tagged PFC SOM/GABA terminals in LPO and the LH induced nesting and NREM sleep respectively. Our findings provide a circuit link for how the PFC responds to sleep deprivation by coordinating sleep preparatory behavior and subsequent sleep.
Yu X, Ba W, Zhao G, et al., 2020, Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior., Molecular Psychiatry, ISSN: 1359-4184
Ma Y, Miracca G, Yu X, et al., 2019, Galanin neurons unite sleep homeostasis and α2-adrenergic sedation, Current Biology, Vol: 29, Pages: 3315-3322.e3, ISSN: 1879-0445
Our urge to sleep increases with time spent awake, until sleep becomes inescapable. The sleep following sleep deprivation is longer and deeper, with an increased power of delta (0.5 - 4 Hz) oscillations, a phenomenon termed sleep homeostasis [1-4]. Although widely-expressed genes regulate sleep homeostasis [1, 4-10], and the process is tracked by somnogens and phosphorylation [1, 3, 7, 11-14], at the circuit level sleep homeostasis has remained mysterious. Previously we found that sedation induced with 2 adrenergic agonists (e.g. dexmedetomidine) and sleep homeostasis both depend on the preoptic (PO) hypothalamus [15, 16]. Dexmedetomidine, increasingly used for long-term sedation in intensive care units , induces a NREM-like sleep but with undesirable hypothermia [18, 19]. Within the PO, various neuronal subtypes (e.g. GABA/galanin and glutamate/NOS1) induce NREM sleep [20-22] and concomitant body cooling [21, 22]. This could be because NREM sleep’s restorative effects depend on lower body temperature [23, 24]. Here, we show that mice with lesioned PO galanin neurons have reduced sleep homeostasis: in the recovery sleep following sleep deprivation, there is a diminished increase in delta power, and the mice catch up little on lost sleep. Furthermore, dexmedetomidine cannot induce high-power delta oscillations or sustained hypothermia. Some hours after dexmedetomidine administration to wild-type mice there is a rebound in delta power when they enter normal NREM sleep, reminiscent of emergence from torpor. This delta rebound is reduced in mice lacking PO galanin neurons. Thus, sleep homeostasis and dexmedetomidine-induced sedation require PO galanin neurons and likely share common mechanisms.
Yu X, Ma Y, Harding EC, et al., 2019, Corrigendum: Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness., Sleep, Vol: 42
Yu X, Ba W, Zhao G, et al., 2019, Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior, bioRxiv.org
Abstract The ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTA Vgat ) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTA Vgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleep-deprived baseline, suggesting that the sleep homeostasis process was bypassed. The mania-like behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTA Vgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTA Vgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTA Vgat neurons are centrally positioned to help set an animal’s (and human’s) level of mental and physical activity. Inputs that inhibit VTA Vgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTA Vgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).
Yu X, Ma Y, Harding E, et al., 2019, Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness, Sleep, Vol: 42, Pages: 1-13, ISSN: 0161-8105
Acute chemogenetic inhibition of histamine (HA) neurons in adult mice induced nonrapid eye movement (NREM) sleep with an increased delta power. By contrast, selective genetic lesioning of HA neurons with caspase in adult mice exhibited a normal sleep–wake cycle overall, except at the diurnal start of the lights-off period, when they remained sleepier. The amount of time spent in NREM sleep and in the wake state in mice with lesioned HA neurons was unchanged over 24 hr, but the sleep–wake cycle was more fragmented. Both the delayed increase in wakefulness at the start of the night and the sleep–wake fragmentation are similar phenotypes to histidine decarboxylase knockout mice, which cannot synthesize HA. Chronic loss of HA neurons did not affect sleep homeostasis after sleep deprivation. However, the chronic loss of HA neurons or chemogenetic inhibition of HA neurons did notably reduce the ability of the wake-promoting compound modafinil to sustain wakefulness. Thus, part of modafinil’s wake-promoting actions arise through the HA system.
Yu X, Li W, Ma Y, et al., 2019, GABA and glutamate neurons in the VTA regulate sleep and wakefulness., Nat Neurosci, Vol: 22, Pages: 106-119
We screened for novel circuits in the mouse brain that promote wakefulness. Chemogenetic activation experiments and electroencephalogram recordings pointed to glutamatergic/nitrergic (NOS1) and GABAergic neurons in the ventral tegmental area (VTA). Activating glutamatergic/NOS1 neurons, which were wake- and rapid eye movement (REM) sleep-active, produced wakefulness through projections to the nucleus accumbens and the lateral hypothalamus. Lesioning the glutamate cells impaired the consolidation of wakefulness. By contrast, activation of GABAergic VTA neurons elicited long-lasting non-rapid-eye-movement-like sleep resembling sedation. Lesioning these neurons produced an increase in wakefulness that persisted for at least 4 months. Surprisingly, these VTA GABAergic neurons were wake- and REM sleep-active. We suggest that GABAergic VTA neurons may limit wakefulness by inhibiting the arousal-promoting VTA glutamatergic and/or dopaminergic neurons and through projections to the lateral hypothalamus. Thus, in addition to its contribution to goal- and reward-directed behaviors, the VTA has a role in regulating sleep and wakefulness.
Harding E, Yu X, Miao A, et al., 2018, A neuronal hub binding sleep initiation and body cooling in response to a warm external stimulus, Current Biology, Vol: 28, Pages: 2263-2273.e4, ISSN: 1879-0445
Mammals, including humans, prepare for sleep by nesting and curling up, creating microclimates of skin warmth. To address if external warmth induces sleep through defined circuitry, we used c-Fos-dependent activity-tagging, which captures populations of activated cells, and allows them to be reactivated to test their physiological role. External warming tagged two principal groups of neurons in the MnPO/MPO hypothalamic area. GABA neurons located mainly in MPO produced NREM sleep but no body temperature decrease. Nitrergic/glutamatergic neurons in MnPO/MPO induced both body cooling and NREM sleep. This circuitry explains how skin warming induces sleep, and why the maximal rate of core body cooling positively correlates with sleep onset. Thus, the pathways that promote NREM-sleep, reduced energy expenditure, and body cooling are inextricably linked, commanded by the same neurons. This implies that one function of NREM sleep is to lower brain temperature and/or conserve energy.
Gelegen C, Miracca G, Ran M, et al., 2018, Excitatory pathways from the lateral habenula enable propofol-induced sedation, Current Biology, Vol: 28, Pages: 580-587.e5, ISSN: 1879-0445
The lateral habenula has been widely studied for its contribution in generating reward-related behaviors [1 ; 2]. We have found that this nucleus plays an unexpected role in the sedative actions of the general anesthetic propofol. The lateral habenula is a glutamatergic, excitatory hub that projects to multiple targets throughout the brain, including GABAergic and aminergic nuclei that control arousal [3; 4 ; 5]. When glutamate release from the lateral habenula in mice was genetically blocked, the ability of propofol to induce sedation was greatly diminished. In addition to this reduced sensitivity to propofol, blocking output from the lateral habenula caused natural non-rapid eye movement (NREM) sleep to become highly fragmented, especially during the rest (“lights on”) period. This fragmentation was largely reversed by the dual orexinergic antagonist almorexant. We conclude that the glutamatergic output from the lateral habenula is permissive for the sedative actions of propofol and is also necessary for the consolidation of natural sleep.
Yu X, Franks N, Wisden W, 2018, Sleep and sedative states induced by targeting the histamine and noradrenergic systems, Frontiers in Neural Circuits, Vol: 12, ISSN: 1662-5110
Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABAA receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure—it is used for long term sedation in hospital intensive care units—under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another α2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry.
Wisden W, Yu X, Franks NP, 2017, GABA Receptors and the Pharmacology of Sleep, Handb Exp Pharmacol, Vol: 253, Pages: 279-304, ISSN: 0171-2004
Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABAA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABAA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABAA receptors, continue to be some of the most effective compounds to treat primary insomnia.
Brickley SG, Ye Z, Yu X, et al., 2017, Fast and slow inhibition in the visual thalamus is influenced by allocating GABAA receptors with different gamma subunits, Frontiers in Cellular Neuroscience, Vol: 11, ISSN: 1662-5102
Cell-type specific differences in the kinetics of inhibitory postsynaptic conductance changes (IPSCs) are believed to impact upon network dynamics throughout the brain. Much attention has focused on how GABAA receptor (GABAAR) α and β subunit diversity will influence IPSC kinetics, but less is known about the influence of the γ subunit. We have examined whether GABAAR γ subunit heterogeneity influences IPSC properties in the thalamus. The γ2 subunit gene was deleted from GABAARs selectively in the dorsal lateral geniculate nucleus (dLGN). The removal of the γ2 subunit from the dLGN reduced the overall spontaneous IPSC (sIPSC) frequency across all relay cells and produced an absence of IPSCs in a subset of relay neurons. The remaining slower IPSCs were both insensitive to diazepam and zinc indicating the absence of the γ2 subunit. Because these slower IPSCs were potentiated by methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), we propose these IPSCs involve γ1 subunit-containing GABAAR activation. Therefore, γ subunit heterogeneity appears to influence the kinetics of GABAAR-mediated synaptic transmission in the visual thalamus in a cell-selective manner. We suggest that activation of γ1 subunit-containing GABAARs give rise to slower IPSCs in general, while faster IPSCs tend to be mediated by γ2 subunit-containing GABAARs.
Jager P, Ye Z, Yu X, et al., 2016, Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus, Nature Communications, Vol: 7, ISSN: 2041-1723
The release of GABA from local interneurons in the dorsal lateral geniculate nucleus (dLGN-INs) provides inhibitory control during visual processing within the thalamus. It is commonly assumed that this important class of interneurons originates from within the thalamic complex, but we now show that during early postnatal development Sox14/Otx2-expressing precursor cells migrate from the dorsal midbrain to generate dLGN-INs. The unexpected extra-diencephalic origin of dLGN-INs sets them apart from GABAergic neurons of the reticular thalamic nucleus. Using optogenetics we show that at increased firing rates tectal-derived dLGN-INs generate a powerful form of tonic inhibition that regulates the gain of thalamic relay neurons through recruitment of extrasynaptic high-affinity GABAA receptors. Therefore, by revising the conventional view of thalamic interneuron ontogeny we demonstrate how a previously unappreciated mesencephalic population controls thalamic relay neuron excitability.
Wisden W, Uygun DS, Ye Z, et al., 2016, Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons, Journal of Neuroscience, Vol: 36, Pages: 11171-11184, ISSN: 0270-6474
Zolpidem, a GABAA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABAA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABAA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep.
Wisden W, Yu X, Ye Z, et al., 2016, Histamine and gamma-amino butyric acid co-transmission promotes arousal, 23rd Congress of the European-Sleep-Research-Society, Publisher: WILEY-BLACKWELL, Pages: 26-26, ISSN: 0962-1105
Yu X, Zecharia A, Zhang Z, et al., 2015, A LOCAL CIRCADIAN CLOCK IN HISTAMINERGIC NEURONS INFLUENCES SLEEP ARCHITECTURE, 44th Annual Meeting of the European-Histamine-Research-Society (EHRS), Publisher: SPRINGER BASEL AG, Pages: S20-S20, ISSN: 1023-3830
Yu X, Zhiwen Y, Houston CM, et al., 2015, Wakefulness is governed by GABA and histamine co-transmission, Neuron, Vol: 87, Pages: 164-178, ISSN: 0896-6273
Histaminergic neurons in the tuberomammilary nucleus (TMN) of the hypothalamus form a widely projecting, wake-active network that sustains arousal. Yet most histaminergic neurons contain GABA. Selective siRNA knockdown of the vesicular GABA transporter (vgat, SLC32A1) in histaminergic neurons produced hyperactive mice with an exceptional amount of sustained wakefulness. Ablation of the vgat gene throughout the TMN further sharpened this phenotype. Optogenetic stimulation in the caudate-putamen and neocortex of “histaminergic” axonal projections from the TMN evoked tonic (extrasynaptic) GABAA receptor Cl− currents onto medium spiny neurons and pyramidal neurons. These currents were abolished following vgat gene removal from the TMN area. Thus wake-active histaminergic neurons generate a paracrine GABAergic signal that serves to provide a brake on overactivation from histamine, but could also increase the precision of neocortical processing. The long range of histamine-GABA axonal projections suggests that extrasynaptic inhibition will be coordinated over large neocortical and striatal areas.
Zhang Z, Ferretti V, Guentan I, et al., 2015, Neuronal ensembles sufficient for recovery sleep and the sedative actions of alpha(2) adrenergic agonists, Nature Neuroscience, Vol: 18, Pages: 553-561, ISSN: 1546-1726
Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic-induced sedation and loss of righting reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the α2 adrenergic receptor agonist dexmedetomidine, we found that sedation and LORR were in fact distinct states, requiring different brain areas: the preoptic hypothalamic area and locus coeruleus (LC), respectively. Selective knockdown of α2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembled the deep recovery sleep that follows sleep deprivation. We used TetTag pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases, non-rapid eye movement sleep, with the accompanying drop in body temperature, was recapitulated. Thus, α2 adrenergic receptor–induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.
Shen N, Jiang S, Lu J-M, et al., 2015, The Constitutive Activation of Egr-1/C/EBPa Mediates the Development of Type 2 Diabetes Mellitus by Enhancing Hepatic Gluconeogenesis, AMERICAN JOURNAL OF PATHOLOGY, Vol: 185, Pages: 513-523, ISSN: 0002-9440
Wisden W, Yu X, Zecharia A, et al., 2014, Circadian Factor BMAL1 in Histaminergic Neurons Regulates Sleep Architecture, Current Biology, Vol: 24, Pages: 2838-2844, ISSN: 1879-0445
Circadian clocks allow anticipation of daily environmental changes [ 1 ]. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body [ 1 ]. Although some peripheral clocks have established roles [ 1 ], it is unclear what local brain clocks do [ 2, 3 ]. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset [ 4–6 ]; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness [ 7–11 ]. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3 [ 12 ]) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN.
Zecharia AY, Yu X, Götz T, et al., 2012, GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness., J Neurosci, Vol: 32, Pages: 13062-13075
The activity of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus correlates with an animal's behavioral state and maintains arousal. We examined how GABAergic inputs onto histaminergic neurons regulate this behavior. A prominent hypothesis, the "flip-flop" model, predicts that increased and sustained GABAergic drive onto these cells promotes sleep. Similarly, because of the histaminergic neurons' key hub-like place in the arousal circuitry, it has also been suggested that anesthetics such as propofol induce loss of consciousness by acting primarily at histaminergic neurons. We tested both these hypotheses in mice by genetically removing ionotropic GABA(A) or metabotropic GABA(B) receptors from histidine decarboxylase-expressing neurons. At the cellular level, histaminergic neurons deficient in synaptic GABA(A) receptors were significantly more excitable and were insensitive to the anesthetic propofol. At the behavioral level, EEG profiles were recorded in nontethered mice over 24 h. Surprisingly, GABAergic transmission onto histaminergic neurons had no effect in regulating the natural sleep-wake cycle and, in the case of GABA(A) receptors, for propofol-induced loss of righting reflex. The latter finding makes it unlikely that the histaminergic TMN has a central role in anesthesia. GABA(B) receptors on histaminergic neurons were dispensable for all behaviors examined. Synaptic inhibition of histaminergic cells by GABA(A) receptors, however, was essential for habituation to a novel environment.
Yu X, Shen N, Zhang M-L, et al., 2011, Egr-1 decreases adipocyte insulin sensitivity by tilting PI3K/Akt and MAPK signal balance in mice, EMBO JOURNAL, Vol: 30, Pages: 3754-3765, ISSN: 0261-4189
Shen N, Yu X, Pan F-Y, et al., 2011, An Early Response Transcription Factor, Egr-1, Enhances Insulin Resistance in Type 2 Diabetes with Chronic Hyperinsulinism, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 14508-14515
Xu Y, Chen J, Yu X, et al., 2010, Protective effects of chlorogenic acid on acute hepatotoxicity induced by lipopolysaccharide in mice, INFLAMMATION RESEARCH, Vol: 59, Pages: 871-877, ISSN: 1023-3830
Yu X, Tao W, Jiang F, et al., 2010, Celastrol Attenuates Hypertension-Induced Inflammation and Oxidative Stress in Vascular Smooth Muscle Cells via Induction of Heme Oxygenase-1, AMERICAN JOURNAL OF HYPERTENSION, Vol: 23, Pages: 895-903, ISSN: 0895-7061
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