197 results found
Nollet M, Wisden W, Franks N, Sleep deprivation and stress - a reciprocal relationship, Interface Focus, ISSN: 2042-8901
Clive J, Wisden W, Savolainen V, The de-scent of sexuality: should we smell a rat?, Archives of Sexual Behavior: an interdisciplinary research journal, 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.
Harding E, Franks N, Wisden W, 2019, Sleep and thermoregulation, Current Opinion in Physiology, 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.
Ma Y, Miracca G, Yu X, et al., 2019, Galanin neurons unite sleep homeostasis and alpha2 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.
Hsieh B, Harding E, Wisden W, et al., A miniature neural recording device to investigate sleep and temperature regulation in mice, IEEE Biomedical Circuits and Systems (BioCAS) Conference, Publisher: IEEE
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.
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.
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.
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.
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.
Paul EJ, Kalk E, Tossell K, et 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.
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.
Brickley SG, Wisden W, Franks NP, 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.
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.
Ma S, Hangya B, Leonard CS, et al., 2017, Dual-transmitter systems regulating arousal, attention, learning and memory., Neuroscience and Biobehavioral Reviews, Vol: 85, Pages: 21-33, ISSN: 0149-7634
An array of neuromodulators, including monoamines and neuropeptides, regulate most behavioural and physiological traits. In the past decade, dramatic progress has been made in mapping neuromodulatory circuits, in analysing circuit dynamics, and interrogating circuit function using pharmacogenetic, optogenetic and imaging methods This review will focus on several distinct neural networks (acetylcholine/GABA/glutamate; histamine/GABA; orexin/glutamate; and relaxin-3/GABA) that originate from neural hubs that regulate wakefulness and related attentional and cognitive processes, and highlight approaches that have identified dual transmitter roles in these behavioural functions. Modulation of these different neural networks might be effective treatments of diseases related to arousal/sleep dysfunction and of cognitive dysfunction in psychiatric and neurodegenerative disorders.
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, 2016, A tribute to Peter H Seeburg (1944-2016): a founding father of molecular neurobiology, Frontiers in Neuroscience, Vol: 9, ISSN: 1662-4548
On 22nd August 2016, the fields of molecular neurobiology and endocrinology lost one of their pioneers and true giants, Peter Seeburg, who died aged 72, a day after his birthday. His funeral ceremony took place in Heidelberg where he had worked since 1988, first as a professor at the University of Heidelberg (ZMBH) and then since 1996 as a director of the Max Plank Institute (Dept. of Molecular Neurobiology). Many of Peter’s former colleagues, students and postdocs came together with his family members to celebrate his life. Touching eulogies were given by no less than two Nobel prize winners: the physiologist Bert Sakmann, who collaborated with Peter for many years, and the developmental biologist Christiane Nüsslein-Vollhard, who was a friend and fellow PhD student with Peter. His professional contemporary, Heinrich Betz, gave a warm and endearing assessment of Peter’s contributions to the field of molecular neurobiology. One of Peter’s sons, Daniel P. Seeburg, now a neuroradiologist in the USA, and biotechnologist Karoly Nikolics, one of Peter’s friends from the days of Genentech, both emotionally summed up the warm and intense character of the man that many of his former students and postdocs knew.
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.
Leppa E, Linden A-M, Aller MI, et al., 2016, Increased motor-impairing effects of the neuroactive steroid sregnanolone in mice with targeted inactivation of the GABA(A) seceptor gamma 2 subunit in the cerebellum, Frontiers in Pharmacology, Vol: 7, ISSN: 1663-9812
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABAA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior.
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.
Steinberg EA, Wafford KA, Brickley SG, et al., 2015, The role of K-2P channels in anaesthesia and sleep, Pflugers Archiv-European Journal of Physiology, Vol: 467, Pages: 907-916, ISSN: 1432-2013
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
Wisden W, Yu X, Zecharia A, et al., 2014, Circadian Factor BMAL1 in Histaminergic Neurons Regulates Sleep Architecture, Current Biology, Vol: 24, Pages: 1-7, 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.
Baker R, Gent TC, Yang Q, et al., 2014, Altered Activity in the Central Medial Thalamus Precedes Changes in the Neocortex during Transitions into Both Sleep and Propofol Anesthesia, JOURNAL OF NEUROSCIENCE, Vol: 34, Pages: 13326-13335, ISSN: 0270-6474
Gelegen C, Gent TC, Ferretti V, et al., 2014, Staying awake - a genetic region that hinders alpha(2) adrenergic receptor agonist-induced sleep, EUROPEAN JOURNAL OF NEUROSCIENCE, Vol: 40, Pages: 2311-2319, ISSN: 0953-816X
Galliano E, Potters J-W, Elgersma Y, et al., 2013, Synaptic Transmission and Plasticity at Inputs to Murine Cerebellar Purkinje Cells Are Largely Dispensable for Standard Nonmotor Tasks, JOURNAL OF NEUROSCIENCE, Vol: 33, Pages: 12599-12618, ISSN: 0270-6474
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