Identifying the Brain Circuits that Regulate Pain-Induced Sleep Disturbances.

Pain therapies that alleviate both pain and sleep disturbances may be the most effective for pain relief, as both chronic pain and sleep loss render the opioidergic system, targeted by opioids, less sensitive and effective for analgesia. Therefore, we first studied the link between sleep disturbances and the activation of nociceptors in two acute pain models. Activation of nociceptors in both acute inflammatory (AIP) and opto-pain models led to sleep loss, decreased sleep spindle density, and increased sleep fragmentation that lasted 3 to 6 hours.

A hypothalamic circuit for circadian regulation of corticosterone secretion.

The secretion of cortisol in humans and corticosterone (Cort) in rodents follows a daily rhythm which is important in readying the individual for the daily active cycle and is impaired in chronic depression. This rhythm is orchestrated by the suprachiasmatic nucleus (SCN) which governs the activity of neurons in the paraventricular nucleus of the hypothalamus that produce the corticotropin-releasing hormone (PVH neurons). The dorsomedial nucleus of the hypothalamus (DMH) serves as a crucial intermediary, being innervated by the SCN both directly and via relays in the subparaventricular zone, and projecting axons to the PVH, thereby exerting influence over the cortisol/corticosterone rhythm.

Lateral parabrachial FoxP2 neurons regulate respiratory responses to hypercapnia.

About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related peptide (CGRP), and cause forebrain arousal. We report here, in male mice, that most of the remaining CO-responsive neurons in the adjacent central lateral (PBcl) and Kölliker-Fuse (KF) PB subnuclei express the transcription factor FoxP2 and many of these neurons project to respiratory sites in the medulla. PBcl neurons show increased intracellular calcium during wakefulness and REM sleep and in response to elevated CO during NREM sleep.

Neural Control of REM Sleep and Motor Atonia: Current Perspectives.

Purpose Of Review: Since the formal discovery of rapid eye movement (REM) sleep in 1953, we have gained a vast amount of knowledge regarding the specific populations of neurons, their connections, and synaptic mechanisms regulating this stage of sleep and its accompanying features. This article discusses REM sleep circuits and their dysfunction, specifically emphasizing recent studies using conditional genetic tools.

Recent Findings: Sublaterodorsal nucleus (SLD) in the dorsolateral pons, especially the glutamatergic subpopulation in this region (SLD), are shown to be indispensable for REM sleep.

Prolonged activation of EP3 receptor-expressing preoptic neurons underlies torpor responses.

Many species use a temporary drop in body temperature and metabolic rate (torpor) as a strategy to survive food scarcity. A similar profound hypothermia is observed with activation of preoptic neurons that express the neuropeptides Pituitary Adenylate-Cyclase-Activating Polypeptide (PACAP), Brain Derived Neurotrophic Factor (BDNF), or Pyroglutamylated RFamide Peptide (QRFP), the vesicular glutamate transporter, Vglut2 or the leptin receptor (LepR), estrogen 1 receptor (Esr1) or prostaglandin E receptor 3 (EP3R) in mice. However, most of these genetic markers are found on multiple populations of preoptic neurons and only partially overlap with one another.

Lateral parabrachial FoxP2 neurons regulate respiratory responses to hypercapnia.

Although CGRP neurons in the external lateral parabrachial nucleus (PBel neurons) are critical for cortical arousal in response to hypercapnia, activating them has little effect on respiration. However, deletion of all Vglut2 expressing neurons in the PBel region suppresses both the respiratory and arousal response to high CO2. We identified a second population of non-CGRP neurons adjacent to the PBel group in the central lateral, lateral crescent and Kölliker-Fuse parabrachial subnuclei that are also activated by CO2 and project to the motor and premotor neurons that innvervate respiratory sites in the medulla and spinal cord.

Glutamatergic pedunculopontine tegmental neurons control wakefulness and locomotion via distinct axonal projections.

Study Objectives: The pedunculopontine tegmental (PPT) nucleus is implicated in many brain functions, ranging from sleep/wake control and locomotion, to reward mechanisms and learning. The PPT contains cholinergic, GABAergic, and glutamatergic neurons with extensive ascending and descending axonal projections. Glutamatergic PPT (PPTvGlut2) neurons are thought to promote wakefulness, but the mechanisms through which this occurs are unknown.

Orexin neurons inhibit sleep to promote arousal.

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus.

Chronic circadian disruption on a high-fat diet impairs glucose tolerance.

Background: Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity, diabetes, and other cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods.

Methods: We investigated the effects of recurrent circadian disruption (RCD) on glucose metabolism in C57BL/6 mice and in human participants exposed to non-24-h light-dark (LD) schedules vs.

Sleep-Wake Control by Melanin-Concentrating Hormone (MCH) Neurons: a Review of Recent Findings.

Purpose Of The Review: Melanin-concentrating hormone (MCH)-expressing neurons located in the lateral hypothalamus are considered as an integral component of sleep-wake circuitry. However, the precise role of MCH neurons in sleep-wake regulation has remained unclear, despite several years of research employing a wide range of techniques. We review recent data on this aspect, which are mostly inconsistent, and propose a novel role for MCH neurons in sleep regulation.

Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations.

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCN) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCN neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCN neurons may regulate LMA rhythms.

Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals.

During obstructive sleep apnea, elevation of CO during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBel neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia.

EP3R-Expressing Glutamatergic Preoptic Neurons Mediate Inflammatory Fever.

Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPO neurons). To investigate the identity of MnPO neurons, we first used hybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons.

An Inhibitory Lateral Hypothalamic-Preoptic Circuit Mediates Rapid Arousals from Sleep.

Among the neuronal populations implicated in sleep-wake control, the ventrolateral preoptic (VLPO) nucleus has emerged as a key sleep-promoting center. However, the synaptic drives that regulate the VLPO to control arousal levels in vivo have not to date been identified. Here, we show that sleep-promoting galaninergic neurons within the VLPO nucleus, defined pharmacologically and by single-cell transcript analysis, are postsynaptic targets of lateral hypothalamic GABAergic (LH) neurons and that activation of this pathway in vivo rapidly drives wakefulness.

Regulation of hippocampal dendritic spines following sleep deprivation.

Accumulating evidence supports the role of sleep in synaptic plasticity and memory consolidation. One line of investigation, the synaptic homeostasis hypothesis, has emphasized the increase in synaptic strength during waking, and compensatory downsizing of (presumably less frequently used) synapses during sleep. Conversely, other studies have reported downsizing and loss of dendritic spines following sleep deprivation.

Lateral hypothalamic neurotensin neurons promote arousal and hyperthermia.

Sleep and wakefulness are greatly influenced by various physiological and psychological factors, but the neuronal elements responsible for organizing sleep-wake behavior in response to these factors are largely unknown. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing the neuropeptide neurotensin (Nts) is critical for orchestrating sleep-wake responses to acute psychological and physiological challenges or stressors. We show that selective activation of NtsLH neurons with chemogenetic or optogenetic methods elicits rapid transitions from non-rapid eye movement (NREM) sleep to wakefulness and produces sustained arousal, higher locomotor activity (LMA), and hyperthermia, which are commonly observed after acute stress exposure.

Ventrolateral periaqueductal gray mediates rapid eye movement sleep regulation by melanin-concentrating hormone neurons.

Neurons containing melanin-concentrating hormone (MCH) in the lateral hypothalamic area (LH) have been shown to promote rapid eye movement sleep (REMs) in mice. However, the downstream neural pathways through which MCH neurons influence REMs remained unclear. Because MCH neurons are considered to be primarily inhibitory, we hypothesized that these neurons inhibit the midbrain 'REMs-suppressing' region consisting of the ventrolateral periaqueductal gray and the lateral pontine tegmentum (vlPAG/LPT) to promote REMs.

Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice.

The preoptic area (POA) is necessary for sleep, but the fundamental POA circuits have remained elusive. Previous studies showed that galanin (GAL)- and GABA-producing neurons in the ventrolateral preoptic nucleus (VLPO) express cFos after periods of increased sleep and innervate key wake-promoting regions. Although lesions in this region can produce insomnia, high frequency photostimulation of the POA neurons was shown to paradoxically cause waking, not sleep.

Melanin-concentrating hormone neurons promote rapid eye movement sleep independent of glutamate release.

Neurons containing melanin-concentrating hormone (MCH) in the posterior lateral hypothalamus play an integral role in rapid eye movement sleep (REMs) regulation. As MCH neurons also contain a variety of other neuropeptides [e.g.

Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy.

The lateral hypothalamus contains neurons producing orexins that promote wakefulness and suppress REM sleep as well as neurons producing melanin-concentrating hormone (MCH) that likely promote REM sleep. Narcolepsy with cataplexy is caused by selective loss of the orexin neurons, and the MCH neurons appear unaffected. As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy.

Colon Carcinoma Presenting as Bacteremia and Liver Abscess.

A collection of dead white blood cells within the liver is called a liver abscess, and pyogenic liver abscess (PLA) is the most common type. PLA is commonly associated with biliary tract infections. However, in this case report, we present a rare cause of bacteremia and PLA which is associated with a carcinoma of the colon at the splenic flexure.

Splenic Infarct and Pulmonary Embolism as a Rare Manifestation of Cytomegalovirus Infection.

Cytomegalovirus (CMV) is a type of herpes infection that has a characteristic feature of maintaining lifelong latency within the host cell. CMV manifestations can cover a broad spectrum from fever to as severe as pancytopenia, hepatitis, retinitis, meningoencephalitis, Guillain-Barre syndrome, pneumonia, and thrombosis. Multiple case reports of thrombosis associated with CMV have been reported.

Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma.

Unlabelled: Euglycemic diabetic ketoacidosis (EDKA) is a clinical triad comprising increased anion gap metabolic acidosis, ketonemia or ketonuria and normal blood glucose levels <200 mg/dL. This condition is a diagnostic challenge as euglycemia masquerades the underlying diabetic ketoacidosis. Thus, a high clinical suspicion is warranted, and other diagnosis ruled out.

Review of Infectious Etiology of Acute Pancreatitis.

While gallstones and alcoholism are widely known to be the most common causative agents of acute pancreatitis, about 10% of cases are thought to be caused by infectious microorganisms. These microorganisms include viruses (e.g.