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Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D 1 receptor (D 1 R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D 1 R neurons. Optogenetic activation of NAc D 1 R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D 1 R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D 1 R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D 1 R neuron circuits are essential for the induction and maintenance of wakefulness. The nucleus accumbens regulates many behaviours that depend on arousal. Here the authors show that dopamine D 1 receptor neurons in the nucleus accumbens can directly regulate wakefulness.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

Rapid eye movement (REM) sleep disturbances are prevalent in various psychiatric disorders. However, the neural circuits that regulate REM sleep remain poorly understood. Here, we found that in male mice, optogenetic activation of rostromedial tegmental nucleus (RMTg) GABAergic neurons immediately converted REM sleep to arousal and then initiated non-REM (NREM) sleep. Conversely, laser-mediated inactivation completely converted NREM to REM sleep and prolonged REM sleep duration. The activity of RMTg GABAergic neurons increased to a high discharge level at the termination of REM sleep. RMTg GABAergic neurons directly converted REM sleep to wakefulness and NREM sleep via inhibitory projections to the laterodorsal tegmentum (LDT) and lateral hypothalamus (LH), respectively. Furthermore, LDT glutamatergic neurons were responsible for the REM sleep-wake transitions following photostimulation of the RMTg GABA -LDT circuit. Thus, RMTg GABAergic neurons are essential for suppressing the induction and maintenance of REM sleep. The neural circuits regulating REM sleep are poorly understood. The authors reveal that GABAergic neurons in the rostromedial tegmental nucleus suppress the onset and maintenance of REM sleep, and that projections of these neurons to the LDT and LH mediate distinct REM sleep transitions.

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2′-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D1 and D2 receptors and GABAA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.

Increasing evidence has revealed that the rostromedial tegmental area (RMTg) mediates many behaviors, including sleep and addiction. However, presynaptic patterns governing the activity of γ-aminobutyric acid-releasing (GABAergic) neurons, the main neuronal type in the RMTg, have not been defined. Here, we used cell-type-specific retrograde trans-synaptic rabies viruses to map and quantify the monosynaptic afferents to RMTg GABAergic neurons in mouse whole brains. We identified 71 ascending projection brain regions. Sixty-eight percent of the input neurons arise from the ipsilateral and 32% from the contralateral areas of the brain. The first three strongest projection regions were the ipsilateral lateral hypothalamus, zone incerta, and contralateral pontine reticular nucleus. Immunohistochemistry imaging showed that the input neurons in the dorsal raphe, laterodorsal tegmentum, and dorsal part of zone incerta were colocalized with serotoninergic, cholinergic, and neuronal nitric oxide synthetase-expressing neurons, respectively. However, in the lateral hypothalamus, a few input neurons innervating RMTg GABAergic neurons colocalized orexinergic neurons but lacked colocalization of melanin-concentrating hormone neurons. Our findings provide anatomical evidence to understand how RMTg GABAergic neurons integrate diverse information to exert varied functions.

Synchronized electroencephalogram (EEG) activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R) and dopamine (DA) D1 and D2 receptors (D1Rs and D2Rs) on modafinil-induced desynchronization in mice. Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p.) completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg) and the D2R antagonist raclopride (2 mg/kg, i.p.). These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.

The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on μ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep-wake behavior and addiction.

Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A2A receptors (A2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A2AR neurons. In addition, chemogenetic inhibition of striatal A2AR neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A2AR neuron/GPe PV neuron circuit in sleep control.

Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D receptor (D R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D R neurons. Optogenetic activation of NAc D R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D R neuron circuits are essential for the induction and maintenance of wakefulness.

To the Editor：The most frequently reported adverse event of pemetrexed was myelosuppression.Here,we reported a patient with advanced lung adenocarcinoma showing pemetrexed-associated ischemic colitis.