Armodafinil-induced wakefulness in animals with ventrolateral preoptic lesions

Armodafinil is the pharmacologically active R-enantiomer of modafinil, a widely prescribed wake-promoting agent used to treat several sleep-related disorders including excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Remarkably, however, the neuronal circuitry through which modafinil exerts its wake-promoting effects remains unresolved. In the present study, we sought to determine if the wake-promoting effects of armodafinil are mediated, at least in part, by inhibiting the sleep-promoting neurons of the ventrolateral preoptic (VLPO) nucleus. To do so, we measured changes in waking following intraperitoneal administration of armodafinil (200 mg/kg) or the psychostimulant methamphetamine (1 mg/kg) in rats with cell-body specific lesion of the VLPO. Rats with histologically confirmed lesions of the VLPO demonstrated a sustained increase in wakefulness at baseline, but the increase in wakefulness following administration of both armodafinil and methamphetamine was similar to that of intact animals. These data suggest that armodafinil increases wakefulness by mechanisms that extend beyond inhibition of VLPO neurons

Role of Basal Ganglia in Sleep–Wake Regulation: Neural Circuitry and Clinical Significance

Researchers over the last decade have made substantial progress toward understanding the roles of dopamine and the basal ganglia (BG) in the control of sleep–wake behavior. In this review, we outline recent advancements regarding dopaminergic modulation of sleep through the BG and extra-BG sites. Our main hypothesis is that dopamine promotes sleep by its action on the D2 receptors in the BG and promotes wakefulness by its action on D1 and D2 receptors in the extra-BG sites. This hypothesis implicates dopamine depletion in the BG (such as in Parkinson's disease) in causing frequent nighttime arousal and overall insomnia. Furthermore, the arousal effects of psychostimulants (methamphetamine, cocaine, and modafinil) may be linked to the ventral periaquductal gray (vPAG) dopaminergic circuitry targeting the extra-BG sleep–wake network

Brainstem and Spinal Cord Circuitry Regulating REM Sleep and Muscle Atonia

Previous work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM) sleep.To determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre) into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA-glycine transporter (VGAT) genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD) and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT) and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT) are not critically involved in REM sleep control.These findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD)

Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1

Brown adipose tissue (BAT) can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1)1,2. Thermogenesis from BAT and beige adipose can combat obesity and diabetes3, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Herein we show that acutely activated BAT thermogenesis is defined by a substantial increase in mitochondrial reactive oxygen species (ROS) levels. Remarkably, this process supports in vivo BAT thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole body energy expenditure. We further establish that thermogenic ROS alter BAT cysteine thiol redox status to drive increased respiration, and Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine nucleotide inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify BAT mitochondrial ROS induction as a mechanism that drives UCP1-dependent thermogenesis and whole body energy expenditure, which opens the way to develop improved therapeutic strategies for combating metabolic disorders

Lateral hypothalamic neurotensin neurons_PLoS Biology_2019

Data Set for Fumito et al., PLoS Biology publicatio

To sleep or not to sleep – Effects on memory in normal aging and disease

Sleep behavior undergoes significant changes across the lifespan, and aging is associated with marked alterations in sleep amounts and quality. The primary sleep changes in healthy older adults include a shift in sleep timing, reduced slow-wave sleep, and impaired sleep maintenance. However, neurodegenerative and psychiatric disorders are more common among the elderly, which further worsen their sleep health. Irrespective of the cause, insufficient sleep adversely affects various bodily functions including energy metabolism, mood, and cognition. In this review, we will focus on the cognitive changes associated with inadequate sleep during normal aging and the underlying neural mechanisms

Evaluation of electronic properties, molecular profiling, bioactivity score, anti-microbial activity and quantum computational studies on methyl (2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)sulfonamide]methyl}-3-[4-(propan-2-yl)phenyl]prop-2-enoate

This analysis was conducted to evaluate the electronic properties and biological significance of the headline molecule. By means of DFT method, geometrical, vibrational and biological properties of the headline molecule were evaluated which is an efficient means of determining structure and has a wide range of applications in the field of biological vibrational spectroscopy. Calculating the interaction energy and electron density is carried out via NBO, while determining the energetic site of the molecule is done via Molecular Electrostatic Potential (MEP) and HOMO-LUMO analysis. In this work, calculated the biological activity and drug similarity parameters of the headline compound to design new molecules with good pharmacological characteristics and this investigation will provide leading information

A Comparative Study of Actinidia deliciosa and Garcinia mangostana in Ovariectomy-Induced Osteoporosis in Female Wistar Rats

The present study was designed to evaluate antiosteoporotic activity of the fresh juice mixtures obtained from Actinidia deliciosa and Garcinia mangostana as well as the pericarp extract of Garcinia mangostana on postmenopausal osteoporosis. 3-month-old female Wistar rats were ovariectiomized and the treatment began 14 days after ovariectomy and continued for 40 days. Statistically significant changes were noticed in body weight, ash weight, bone mineral content, and femur length and weight followed by serum evaluation and histopathology of femur bone. Administration of the fresh juice mixtures of the fruits of Actinidia deliciosa and Garcinia mangostana prevented ovariectomy-induced bone loss. The administration of the fresh juice mixtures resulted in an increase in the femur length and weight, followed by an increase in the body weight as well as the calcium content obtained from the ash of the femur bone. It is evident that the fresh juice mixtures can be used as a remedy as well as a prophylactic for the prevention of postmenopausal osteoporosis. The present study showed that the combined effect of the fruit juice mixtures of Actinidia deliciosa and Garcinia mangostana was found to be a better treatment for postmenopausal osteoporosis when compared to the pericarp extract of Garcinia mangostana