Unique infrared thermographic profiles and altered hypothalamic neurochemistry associated with mortality in endotoxic shock.

Neonatal sepsis results in significant morbidity and mortality, but early detection is clinically challenging. In a neonatal rat model of endotoxic shock, we characterised unique infrared thermographic (IRT) profiles in skin temperature that could identify risk of later mortality. Ten-day old rats were placed in a thermally stable isolette and IRT images of cranial (T), scapula (T) and rump (T) skin temperature were obtained continuously for 8 h following an intraperitoneal injection of lipopolysaccharide (LPS) or saline.

Asymmetric neuromodulation in the respiratory network contributes to rhythm and pattern generation.

Like other brain circuits, the brainstem respiratory network is continually modulated by neurotransmitters that activate slow metabotropic receptors. In many cases, activation of these receptors only subtly modulates the respiratory motor pattern. However, activation of some receptor types evokes the arrest of the respiratory motor pattern as can occur following the activation of μ-opioid receptors.

Persistent glossopharyngeal nerve respiratory discharge patterns after ponto-medullary transection.

Shape and size of the nasopharyngeal airway is controlled by muscles innervated facial, glossopharyngeal, vagal, and hypoglossal cranial nerves. Contrary to brainstem networks that drive facial, vagal and hypoglossal nerve activities (FNA, VNA, HNA) the discharge patterns and origins of glossopharyngeal nerve activity (GPNA) remain poorly investigated. Here, an in situ perfused brainstem preparation (n=19) was used for recordings of GPNA in relation to phrenic (PNA), FNA, VNA and HNA.

Blood pressure pulsations modulate central neuronal activity via mechanosensitive ion channels.

The transmission of the heartbeat through the cerebral vascular system causes intracranial pressure pulsations. We discovered that arterial pressure pulsations can directly modulate central neuronal activity. In a semi-intact rat brain preparation, vascular pressure pulsations elicited correlated local field oscillations in the olfactory bulb mitral cell layer.

Neuroanatomical frameworks for volitional control of breathing and orofacial behaviors.

Breathing is the only vital function that can be volitionally controlled. However, a detailed understanding how volitional (cortical) motor commands can transform vital breathing activity into adaptive breathing patterns that accommodate orofacial behaviors such as swallowing, vocalization or sniffing remains to be developed. Recent neuroanatomical tract tracing studies have identified patterns and origins of descending forebrain projections that target brain nuclei involved in laryngeal adductor function which is critically involved in orofacial behavior.

The pre-Bötzinger complex is necessary for the expression of inspiratory and post-inspiratory motor discharge of the vagus.

The mammalian three-phase respiratory motor pattern of inspiration, post-inspiration and expiration is expressed in spinal and cranial motor nerve discharge and is generated by a distributed ponto-medullary respiratory pattern generating network. Respiratory motor pattern generation depends on a rhythmogenic kernel located within the pre-Bötzinger complex (pre-BötC). In the present study, we tested the effect of unilateral and bilateral inactivation of the pre-BötC after local microinjection of the GABA receptor agonist isoguvacine (10 mM, 50 nl) on phrenic (PNA), hypoglossal (HNA) and vagal nerve (VNA) respiratory motor activities in an in situ perfused brainstem preparation of rats.

Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse.

Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively.

Sustained Effects of Capsaicin Infusion into the Oropharynx on Swallowing in Perfused Rats.

Objectives: To examine the sustained effects of oropharyngeal capsaicin stimulation on the regulation of swallowing, we recorded the swallowing-related nerve activities during continuous infusion of capsaicin solution into the oropharynx.

Methods: In 33 in situ perfused brainstem preparation of rats, we recorded the activities of the vagus, hypoglossal, and phrenic nerves during fictive swallowing. The interburst intervals (IBIs) of the swallowing-related nerves during sequential pharyngeal swallowing (sPSW) elicited by electrical stimulation of the superior laryngeal nerve (SLN) during concurrent capsaicin stimulation of 10, 1, and 0.

Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for α-Helical Peptidomimetics.

Peptides and peptidomimetics are attractive drug candidates because of their high target specificity and low-toxicity profiles. Developing peptidomimetics using hydrocarbon (HC)-stapling or other stapling strategies has gained momentum because of their high stability and resistance to proteases; however, they have limitations. Here, we take advantage of the α-methyl group and an aromatic phenyl ring in a unique unnatural amino acid, α-methyl-l-phenylalanine (αF), and propose a novel, noncovalent stapling strategy to stabilize peptides.

Effect of pharmacological inhibition of the pontine respiratory group on swallowing interneurons in the dorsal medulla oblongata.

Objectives: To examine the role of neurons of the pontine respiratory group (PRG) overlapping with the Kölliker-Fuse nucleus in the regulation of swallowing, we compared the activity of swallowing motor activities and interneuron discharge in the dorsal swallowing group in the medulla before and after pharmacological inhibition of the PRG.

Methods: In 23 in situ perfused brainstem preparation of rats, we recorded the activities of the vagus (VNA), hypoglossal (HNA), and phrenic nerves (PNA), and swallowing interneurons of the dorsal medulla during fictive swallowing elicited by electrical stimulation of the superior laryngeal nerve or oral water injection. Subsequently, respiratory- and swallow-related motor activities and single unit cell discharge were assessed before and after local microinjection of the GABA-receptor agonist muscimol into the area of PRG ipsilateral to the recording sites of swallowing interneurons.

Advancing respiratory-cardiovascular physiology with the working heart-brainstem preparation over 25 years.

Twenty-five years ago, a new physiological preparation called the working heart-brainstem preparation (WHBP) was introduced with the claim it would provide a new platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of the progress made with the WHBP, some advantages and disadvantages along with potential future applications, and provide photographs and technical drawings of all the customised equipment used for the preparation. Using mice or rats, the WHBP is an in situ experimental model that is perfused via an extracorporeal circuit benefitting from unprecedented surgical access, mechanical stability of the brain for whole cell recording and an uncompromised use of pharmacological agents akin to in vitro approaches.

Loss-of-function and gain-of-function studies refute the hypothesis that tau protein is causally involved in the pathogenesis of Huntington's disease.

Tubulin-associated unit (Tau) is a microtubule-associated protein, whose abnormal phosphorylation and deposition in the brain characterizes a range of neurodegenerative diseases called tauopathies. Recent clinical (post-mortem) and pre-clinical evidence suggests that Huntington's disease (HD), an autosomal dominant neurodegenerative disorder, could be considered as a tauopathy. Studies have found the presence of hyperphosphorylated tau, altered tau isoform ratio and aggregated tau in HD brains.

Firing characteristics of swallowing interneurons in the dorsal medulla during physiologically induced swallowing in perfused brainstem preparation in rats.

Oropharyngeal swallowing is centrally mediated by a swallowing central pattern generator (Sw-CPG) in the medulla oblongata. The activity of the Sw-CPG depends on the sensory inputs determined by physical and chemical bolus properties. Here we investigate the sensory-motor integration during swallowing arising from different sensory sources.

The role of glycinergic inhibition in respiratory pattern formation and cardio-respiratory coupling in rats.

Cardio-respiratory coupling is reflected as respiratory sinus arrhythmia (RSA) and inspiratory-related bursting of sympathetic nerve activity. Inspiratory-related inhibitory and/or postinspiratory-related excitatory drive of cardiac vagal motoneurons (CVMs) can generate RSA. Since respiratory oscillations may depend on synaptic inhibition, we investigated the effects of blocking glycinergic neurotransmission (systemic and local application of the glycine receptor (GlyR) antagonist, strychnine) on the expression of the respiratory motor pattern, RSA and sympatho-respiratory coupling.

Decreased incidence, virus transmission capacity, and severity of COVID-19 at altitude on the American continent.

The coronavirus disease 2019 (COVID-19) outbreak in North, Central, and South America has become the epicenter of the current pandemic. We have suggested previously that the infection rate of this virus might be lower in people living at high altitude (over 2,500 m) compared to that in the lowlands. Based on data from official sources, we performed a new epidemiological analysis of the development of the pandemic in 23 countries on the American continent as of May 23, 2020.

Reciprocal connectivity of the periaqueductal gray with the ponto-medullary respiratory network in rat.

Synaptic activities of the periaqueductal gray (PAG) can modulate or appropriate the respiratory motor activities in the context of behavior and emotion via descending projections to nucleus retroambiguus. However, alternative anatomical pathways for the mediation of PAG-evoked respiratory modulation via core nuclei of the brainstem respiratory network remains only partially described. We injected the retrograde tracer Cholera toxin subunit B (CT-B) in the pontine Kölliker-Fuse nucleus (KFn, n = 5), medullary Bötzinger (BötC, n = 3) and pre-Bötzinger complexes (pre-BötC; n = 3), and the caudal raphé nuclei (n = 3), and quantified the descending connectivity of the PAG targeting these brainstem respiratory regions.

Forebrain projection neurons target functionally diverse respiratory control areas in the midbrain, pons, and medulla oblongata.

Eupnea is generated by neural circuits located in the ponto-medullary brainstem, but can be modulated by higher brain inputs which contribute to volitional control of breathing and the expression of orofacial behaviors, such as vocalization, sniffing, coughing, and swallowing. Surprisingly, the anatomical organization of descending inputs that connect the forebrain with the brainstem respiratory network remains poorly defined. We hypothesized that descending forebrain projections target multiple distributed respiratory control nuclei across the neuroaxis.

Influences of GABAergic Inhibition in the Dorsal Medulla on Contralateral Swallowing Neurons in Rats.

Objectives: We aimed to examine the effect of unilateral inhibition of the medullary dorsal swallowing networks on the activities of swallowing-related cranial motor nerves and swallowing interneurons.

Methods: In 25 juvenile rats, we recorded bilateral vagal nerve activity (VNA) as well as unilateral phrenic and hypoglossal activity (HNA) during fictive swallowing elicited by electrical stimulation of the superior laryngeal nerve during control and following microinjection of the GABA agonist muscimol into the caudal dorsal medulla oblongata in a perfused brainstem preparation. In 20 animals, swallowing interneurons contralateral to the muscimol injection side were simultaneously recorded extracellularly and their firing rates were analyzed during swallowing.

Coping with hypoxemia: Could erythropoietin (EPO) be an adjuvant treatment of COVID-19?

A very recent epidemiological study provides preliminary evidence that living in habitats located at 2500 m above sea level (masl) might protect from the development of severe respiratory symptoms following infection with the novel SARS-CoV-2 virus. This epidemiological finding raises the question of whether physiological mechanisms underlying the acclimatization to high altitude identifies therapeutic targets for the effective treatment of severe acute respiratory syndrome pivotal to the reduction of global mortality during the COVID-19 pandemic. This article compares the symptoms of acute mountain sickness (AMS) with those of SARS-CoV-2 infection and explores overlapping patho-physiological mechanisms of the respiratory system including impaired oxygen transport, pulmonary gas exchange and brainstem circuits controlling respiration.

Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude?

In the present study we analyze the epidemiological data of COVID-19 of Tibet and high-altitude regions of Bolivia and Ecuador, and compare to lowland data, to test the hypothesis that high-altitude inhabitants (+2,500 m above sea-level) are less susceptible to develop severe adverse effects in acute SARS-CoV-2 virus infection. Analysis of available epidemiological data suggest that physiological acclimatization/adaptation that counterbalance the hypoxic environment in high-altitude may protect from severe impact of acute SARS-CoV-2 virus infection. Potential underlying mechanisms such as: (i) a compromised half-live of the virus caused by the high-altitude environment, and (ii) a hypoxia mediated down regulation of angiotensin-converting enzyme 2 (ACE2), which is the main binding target of SARS-CoV-2 virus in the pulmonary epithelium are discussed.

Volumetric mapping of the functional neuroanatomy of the respiratory network in the perfused brainstem preparation of rats.

Key Points: The functional neuroanatomy of the mammalian respiratory network is far from being understood since experimental tools that measure neural activity across this brainstem-wide circuit are lacking. Here, we use silicon multi-electrode arrays to record respiratory local field potentials (rLFPs) from 196-364 electrode sites within 8-10 mm of brainstem tissue in single arterially perfused brainstem preparations with respect to the ongoing respiratory motor pattern of inspiration (I), post-inspiration (PI) and late-expiration (E2). rLFPs peaked specifically at the three respiratory phase transitions, E2-I, I-PI and PI-E2.

Relaxin-3 receptor (RXFP3) activation in the nucleus of the solitary tract modulates respiratory rate and the arterial chemoreceptor reflex in rat.

The neuropeptide relaxin-3 is expressed by the pontine nucleus incertus. Relaxin-3 and synthetic agonist peptides modulate arousal and cognitive processes via activation of the relaxin-family peptide 3 receptor (RXFP3). Despite the presence of RXFP3 in the nucleus of the solitary tract (NTS), the ability of RXFP3 to modulate NTS-mediated cardiorespiratory functions has not been explored.