Imperial College London

Prof. William Wisden F. Med. Sci.

Faculty of Natural SciencesDepartment of Life Sciences

Chair in Molecular Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 9744w.wisden Website CV

 
 
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Location

 

401BSir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

210 results found

Yu X, Zhao G, Wang D, Wang S, Li R, Li A, Wang H, Nollet M, Chun YY, Zhao T, Yustos R, Li H, Zhao J, Li J, Cai M, Vyssotski A, Li Y, Dong H, Franks N, Wisden Wet al., 2022, A specific circuit in the midbrain detects stress and induces restorative sleep, Science, Vol: 377, Pages: 1-10, ISSN: 1095-9203

In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity - dependent tagging revealed a subset of ventral tegmental area GABA-somatostatin (VTAVgat-Sst) cells that sense stress and drive NREM and REM sleep via the lateral hypothalamus, andalso inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTA Vgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTAVgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone levels remained elevated after stress. Thus, aspecific circuit allows animals to restore mental and body functions via sleeping, potentially providing a refined route for treating anxiety disorders.

Journal article

Miracca G, Anuncibay Soto B, Tossell K, Yustos R, Vyssotski A, Franks N, Wisden Wet al., 2022, NMDA receptors in the lateral preoptic hypothalamus are essential for sustaining NREM and REM sleep, The Journal of Neuroscience, Vol: 42, Pages: 5389-5409, ISSN: 0270-6474

The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA26 receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine). By contrast, fragmentation persisted under high sleeppressure produced by sleep deprivation - mice had a high propensity to sleep but woke up. By analyzing changes in delta power, sleep homeostasis (also referred to as “sleep drive”) remained intact after NMDA receptor ablation. We suggest NMDA glutamate receptor activation stabilizes firing of sleep-on neurons, and that mechanisms of sleep maintenance differ from that of the sleep drive itself.

Journal article

Souter EA, Chen Y-C, Zell V, Lallai V, Steinkellner T, Conrad WS, Wisden W, Harris KD, Fowler CD, Hnasko TSet al., 2022, Disruption of VGLUT1 in Cholinergic Medial Habenula Projections Increases Nicotine Self-Administration, ENEURO, Vol: 9

Journal article

Franks NP, Wisden W, 2021, The inescapable drive to sleep: Overlapping mechanisms of sleep and sedation, SCIENCE, Vol: 374, Pages: 556-559, ISSN: 0036-8075

Journal article

Harding EC, Ba W, Zahir R, Yu X, Yustos R, Hsieh B, Lignos L, Vyssotski AL, Merkle FT, Constandinou TG, Franks NP, Wisden Wet al., 2021, Nitric oxide synthase neurons in the preoptic hypothalamus are NREM and REM sleep-active and lower body temperature, Frontiers in Neuroscience, Vol: 15, ISSN: 1662-453X

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 and REM active, especially at the boundary of wake to NREM transitions, and in the later parts of REM bouts, with lower activity during wakefulness. 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 h, 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 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.

Journal article

Yu X, Ba W, Zhao G, Ma Y, Harding EC, Yin L, Wang D, Li H, Zhang P, Shi Y, Yustos R, Vyssotski AL, Wisden W, Franks NP, Dong Het al., 2021, Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior, Molecular Psychiatry, Vol: 26, Pages: 5213-5228, ISSN: 1359-4184

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Journal article

Clive J, Wisden W, Savolainen V, 2021, The de-scent of sexuality: should we smell a rat?, Archives of Sexual Behavior: an interdisciplinary research journal, Vol: 50, Pages: 2283-2288, ISSN: 0004-0002

In their Target Article, Pfau, Jordan, and Breedlove (2019) proposed a connection between the transient receptor potential cation channel 2 gene (TRPC2) and same-sex sexual behavior (SSSB) in primates. This novel theory is an attractive prospect for researchers investigating sexuality in the natural world. The proposal relies on evidence from proximate mechanism studies of TRPC2 knockout (KO) experiments in mice, in which non-functional TPRC2 alters the development of an olfactory sensory structure called the vomeronasal organ (VNO), resulting in an increase of SSSB in both males and females (Axel et al., 2002; Kimchi, Xu, & Dulac, 2007). In combination with an examination of TRPC2 sequence data and evolutionary relationships across primates, Pfau et al. proposed some hypotheses for the fitness consequences of SSSB in primates. Pfau et al. speculated that primates with multi-male/multi-female societies may have evolved via improved social cohesion facilitated by an increase in SSSB, mediated by non-functional TRPC2, and/or pleiotropy between increased SSSB and reduced same-sex aggression. Here, although we support some of these ideas by providing a more complete examination of TRPC2 in primates, we also advocate greater caution when interpreting available data on SSSB.

Journal article

Harding EC, Ba W, Zahir R, Yu X, Yustos R, Hsieh B, Lignos L, Vyssotski AL, Constandinou T, Franks NP, Wisden Wet 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.

Working paper

Yu X, Franks NP, Wisden W, 2021, Brain Clocks, Sleep, and Mood, CIRCADIAN CLOCK IN BRAIN HEALTH AND DISEASE, Vol: 1344, Pages: 71-86, ISSN: 0065-2598

Journal article

Miracca G, Soto BA, Tossell K, Yustos R, Vyssotski AL, Franks NP, Wisden Wet al., 2020, Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

<jats:title>SUMMARY</jats:title><jats:p>The preoptic hypothalamus regulates both NREM and REM sleep. We found that calcium levels in mouse lateral preoptic (LPO) neurons were highest during REM. Deleting the core GluN1 subunit of NMDA receptors from LPO neurons abolished calcium signals during all vigilance states, and the excitatory drive onto LPO neurons was reduced. Mice had less NREM sleep and were incapable of generating conventionally classified REM sleep episodes: cortical theta oscillations were greatly reduced but muscle atonia was maintained. Additionally, mice lacking NMDA receptors in LPO neurons had highly fragmented sleep-wake patterns. The fragmentation persisted even under high sleep pressure produced by sleep deprivation. Nevertheless, the sleep homeostasis process remained intact, with an increase in EEG delta power. The sedative dexmedetomidine and sleeping medication zolpidem could transiently restore consolidated sleep. High sleep-wake fragmentation, but not sleep loss, was also produced by selective GluN1 knock-down in GABAergic LPO neurons. We suggest that NMDA glutamate receptor signalling stabilizes the firing of “GABAergic NREM sleep-on” neurons and is also essential for the theta rhythm in REM sleep.</jats:p>

Journal article

Lignos L, Nollet M, Wisden W, Franks NPet al., 2020, Does sleep deprivation cause stress in mice? A comparison of gentle handling versus novel object presentation sleep deprivation methods, 25th Congress of the European-Sleep-Research-Society (ESRS), Publisher: WILEY, Pages: 195-196, ISSN: 0962-1105

Conference paper

Tossell K, Yu X, Soto BA, Vicente M, Miracca G, Giannos P, Miao A, Hsieh B, Ma Y, Yustos R, Vyssotski A, Constandinou T, Franks N, Wisden Wet 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.

Working paper

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.

Journal article

Nollet M, Wisden W, Franks N, 2020, Sleep deprivation and stress - a reciprocal relationship, Interface Focus, Vol: 10, Pages: 1-11, ISSN: 2042-8901

Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep restriction usually exhibit detrimental physiological responses, while total and prolonged sleep loss could lead to death. The perturbation of sleep homeostasis is usually accompanied by an increase of the hypothalamic-pituitary-adrenal (HPA) axis, leading to a rise of circulating level of stress hormones (e.g., cortisol in humans, corticosterone in rodents). Such hormones follow a circadian release pattern under undisturbed conditions and participate in the regulation of sleep. The investigation of the consequences of sleep deprivation, from molecular changes to behavioural alterations, has been used to study the fundamental functions of sleep. However, the reciprocal relationship between sleep and the activity of the HPA axis is problematic when investigating sleep using traditional sleep-deprivation protocols that can induce stress per se. This is especially true in studies using rodents in which sleep deprivation is achieved by exogenous, and potentially stressful, sensory-motor stimulations that can undoubtedly confuse their conclusions. While more research is needed to explore the mechanisms underlying sleep loss and health, avoiding stress as a confounding factor in sleep-deprivation studies is therefore crucial. This review examines the evidence of the intricate links between sleep and stress in the context of experimental sleep deprivation, and proposes a more sophisticated research framework for sleep-deprivation procedures that could benefit from recent progress in biotechnological tools for precise neuromodulation, such as chemogenetics and optogenetics, as well as improved automated real-time sleep scoring algorithms.

Journal article

Wisden W, Franks NP, 2020, The stillness of sleep., Scienc, Vol: 367, Pages: 366-367, ISSN: 1095-9203

Journal article

Hsieh B, Harding E, Wisden W, Franks N, Constandinou Tet 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.

Conference paper

Ma Y, Miracca G, Yu X, Harding E, Miao A, Yustos R, Vyssotski A, Franks N, Wisden Wet 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 [17], 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.

Journal article

Yu X, Ba W, Zhao G, Ma Y, Harding E, Yin L, Wang D, Shi Y, Vyssotski A, Dong H, Franks N, Wisden Wet al., 2019, Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

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).

Working paper

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.

Journal article

Ma Y, Miracca G, Yu X, Harding EC, Miao A, Yustos R, Vyssotski AL, Franks NP, Wisden Wet al., 2019, Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

<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

Journal article

Yu X, Ma Y, Harding E, Yustos R, Vyssotski A, Franks N, Wisden Wet 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.

Journal article

Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Yet al., 2019, Histamine: neural circuits and new medications, Sleep, Vol: 42, ISSN: 0161-8105

Histamine was first identified in the brain about 50 years ago, but only in the last few years have researchers gained an understanding of how it regulates sleep/wake behavior. We provide a translational overview of the histamine system, from basic research to new clinical trials demonstrating the usefulness of drugs that enhance histamine signaling. The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and like many of the arousal systems, histamine neurons diffusely innervate the cortex, thalamus, and other wake-promoting brain regions. Histamine has generally excitatory effects on target neurons, but paradoxically, histamine neurons may also release the inhibitory neurotransmitter GABA. New research demonstrates that activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation. The number of histamine neurons is increased in narcolepsy, but whether this affects brain levels of histamine is controversial. Of clinical importance, new compounds are becoming available that enhance histamine signaling, and clinical trials show that these medications reduce sleepiness and cataplexy in narcolepsy.

Journal article

Yu X, Li W, Ma Y, Tossell K, Harris J, Harding E, Ba W, Miracca G, Wang D, Li L, Guo J, Chen M, Li Y, Yustos R, Vyssotski A, Burdakov D, Yang Q, Dong H, Franks N, Wisden Wet 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.

Journal article

Paul EJ, Kalk E, Tossell K, Irvine E, Franks NP, Wisden W, Withers DJ, Leiper JM, Ungless MAet al., 2018, nNOS-expressing neurons in the ventral tegmental area and substantia nigra pars compacta, eNeuro, Vol: 5, ISSN: 2373-2822

GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear whether some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesized that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell type-specific virus-based anterograde tracing in mice. We found that nNOS-expressing neurons, in the parabrachial pigmented (PBP) part of the VTA and the SNc were GABAergic and did not make detectable projections, suggesting they may be interneurons. In contrast, nNOS-expressing neurons in the rostral linear nucleus (RLi) were mostly glutamatergic and projected to a number of regions, including the lateral hypothalamus (LH), the ventral pallidum (VP), and the median raphe (MnR) nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically-distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc.

Journal article

Harding E, Yu X, Miao A, Andrews N, Ma Y, Ye Z, Lignos L, Miracca G, Ba W, Yustos R, Vyssotski A, Wisden W, Franks Net 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.

Journal article

Gelegen C, Miracca G, Ran M, Harding E, Ye Z, Yu X, Tossell K, Houston C, Yustos R, Hawkins E, Vyssotski A, Dong H, Wisden W, Franks NPet 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.

Journal article

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.

Journal article

Brickley SG, Wisden W, Franks NP, 2018, Modulation of GABA-A receptor function and sleep, Current Opinion in Physiology, Vol: 2, Pages: 51-57, ISSN: 2468-8673

The intravenous general anaesthetics (propofol & etomidate), the barbiturates, steroids (e.g. alphaxalone, allopregnanalone), the benzodiazepines and the widely prescribed ‘sleeping pill’, the imidazopyridine zolpidem, are all positive allosteric modulators (PAMs) of GABAA receptors. PAMs enhance ongoing GABAergic communication between neurons. For treating primary insomnia, zolpidem remains a gold-standard medication — it reduces the latency to NREM sleep with a rapid onset and short half-life, leading to relatively few hangover effects. In this review, we discuss the role of the different GABAA receptor subtypes in the action of sleep-promoting drugs. Certain neuronal hub areas exert disproportionate effects on the brain's vigilance states. For example, injecting GABAA agonists and PAMs into the mesopontine tegmental anaesthesia area (MPTA) induces an anaesthetic-like state. Similarly, by selectively increasing the GABA drive onto arousal-promoting nuclei, such as the histaminergic neurons in the tuberomammillary nucleus, a more natural NREM-like sleep emerges. Some patients suffering from idiopathic hypersomnia have an unidentified GABAA receptor PAM in their cerebral spinal fluid. Treating these patients with benzodiazepine PAM site antagonists improves their symptoms. More knowledge of endogenous GABAA receptor PAMs could provide insight into sleep physiology.

Journal article

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.

Journal article

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