16 results found
Harding EC, Ba W, Zahir R, et al., 2021, Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature, Publisher: Cold Spring Harbor Laboratory
When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM 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
Harding E, Franks N, Wisden W, 2020, Sleep and thermoregulation, Current Opinion in Physiology, Vol: 15, Pages: 7-13, ISSN: 2468-8673
In homeothermic animals sleep preparatory behaviours often promote thermal efficiency, including warmth-seeking, adopting particular postures (curling up, head tucking) and nest building, all promoting warmer skin microclimates. Skin warmth induces NREM sleep and body cooling via circuitry that connects skin sensation to the preoptic hypothalamus. Coupling sleep induction and lower body temperature could serve to minimise energy expenditure or allow energy reallocation. Cooling during NREM sleep may also induce transcriptional changes in genes whose products facilitate housekeeping functions or measure the time spent sleeping.
Hsieh B, Harding E, Wisden W, et al., 2019, A miniature neural recording device to investigate sleep and temperature regulation in mice, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE, Pages: 1-4
Sleep is an important and ubiquitous process that,despite decades of research, a large part of its underlyingbiological circuity still remain elusive. To conduct research inthis field, many devices capable of recording neural signalssuch as LFP and EEG have been developed. However, most ofthese devices are unsuitable for sleep studies in mice, the mostcommonly used animals, due to their size and weight. Thus, thispaper presents a novel 4 channel, compact ( 2.1cm by 1.7cm )and lightweight ( 3.6g ) neural-logging device that can recordfor 3 days on just two 0.6g zinc air 312 batteries. Instead ofthe typical solution of using multiple platforms, the presenteddevice integrates high resolution EEG, EMG and temperaturerecordings into one platform. The onboard BLE module allowsthe device to be controlled wirelessly as well as stream data in realtime, enabling researchers to check the progress of the recordingwith minimal animal disturbance. The device demonstrates itsability to accurately record EEG and temperature data throughthe long 24 hour in-vivo recordings conducted. The obtainedEEG data could be easily sleep scored and the temperaturesvalues were all within expected physiological range.
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).
Harding E, Franks N, Wisden W, 2019, The temperature dependence of sleep, Frontiers in Neuroscience, Vol: 13, ISSN: 1662-4548
Mammals have evolved a range of behavioural and neurological mechanisms that coordinate cycles of thermoregulation and sleep. Whether diurnal or nocturnal, sleep onset and a reduction in core temperature occur together. Non-rapid eye movement (NREM) sleep episodes are also accompanied by core and brain cooling. Thermoregulatory behaviours, like nest building and curling up, accompany this circadian temperature decline in preparation for sleeping. This could be a matter of simply comfort as animals seek warmth to compensate for lower temperatures. However, in both humans and other mammals, direct skin warming can shorten sleep-latency and promote NREM sleep. We discuss the evidence that body cooling and sleep are more fundamentally connected and that thermoregulatory behaviours, prior to sleep, form warm microclimates that accelerate NREM directly through neuronal circuits. Paradoxically, this warmth might also induce vasodilation and body cooling. In this way, warmth seeking and nesting behaviour might enhance the circadian cycle by activating specific circuits that link NREM initiation to body cooling. We suggest that these circuits explain why NREM onset is most likely when core temperature is at its steepest rate of decline and why transitions to NREM are accompanied by a decrease in brain temperature. This connection may have implications for energy homeostasis and the function of sleep.
<jats:title>Abstract</jats:title><jats:p>Sleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 - 4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of <jats:italic>LPO</jats:italic>-Δ<jats:italic>Gal</jats:italic> mice became heavily fragmented, their average core body temperature permanently increased (by about 2°C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, <jats:italic>LPO</jats:italic>-Δ<jats:italic>Gal</jats:italic> mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite - a decrease in body temperature and becoming maximally sleepy (start of “lights on”). After sleep deprivation sleep homeostasis was largely abolished in <jats:italic>LPO</jats:italic>-Δ<jats:italic>Gal</jats:italic> mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the α2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in b
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, Nature Neuroscience, Vol: 22, Pages: 106-119, ISSN: 1097-6256
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 EC, 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: 0960-9822
Mammals, including humans, prepare for sleep by nesting and/or curling up, creating microclimates of skin warmth. To address whether 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 median preoptic (MnPO)/medial preoptic (MPO) hypothalamic area. GABA neurons located mainly in MPO produced non-rapid eye movement (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. Harding et al. identify nitrergic/glutamatergic neurons in the MnPO-MPO hypothalamus, which after activity tagging by a warm external stimulus induce both sleep and hypothermia when reactivated. This suggests sleep and body cooling are inextricably linked. Reactivating GABAergic neurons, however, induces only sleep.
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.
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.
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.
Jegouzo SAF, Harding EC, Acton O, et al., 2014, Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate, GLYCOBIOLOGY, Vol: 24, Pages: 1291-1300, ISSN: 0959-6658
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