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Brain Pathology (Zurich, Switzerland) Jan 2021Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure-related respiratory dysfunction. Medullary respiratory...
Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure-related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre-Bötzinger complex (pre-BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre-BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post-mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non-epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH-immunoreactive (TH-IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C-fos immunoreactivity was also semi-quantitatively evaluated in these regions. We found no significant difference in the density of TH-IR neurones or labeling index between the groups in all regions. Significantly more TH-IR neurones were present in the DMM region than VLM in non-epilepsy cases only (P < 0.01). Regional variations in TH-IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c-fos labeling in the VLM and MR in SUDEP than non-epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH-IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c-fos neurones compared to control groups which may be relevant to the mechanism of death.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Male; Medulla Oblongata; Middle Aged; Neurons; Sudden Unexpected Death in Epilepsy; Tyrosine 3-Monooxygenase; Young Adult
PubMed: 32852867
DOI: 10.1111/bpa.12891 -
Journal of Stroke and Cerebrovascular... Oct 2022There is a low incidence of the medullary infarctions and sparse data about the vascular territories, as well as a correlation among the anatomic, magnetic resonance...
OBJECTIVE
There is a low incidence of the medullary infarctions and sparse data about the vascular territories, as well as a correlation among the anatomic, magnetic resonance imaging (MRI) and neurologic signs.
MATERIALS AND METHODS
Arteries of the 10 right and left sides of the brain stem were injected with India ink, fixed in formalin and microdissected. The enrolled 34 patients with medullary infarctions underwent a neurologic, MRI and Doppler examination.
RESULTS
Four types of the infarctions were distinguished according to the involved vascular territories. The isolated medial medullary infarctions (MMIs) were present in 14.7%. The complete MMIs comprised one bilateral infarction (2.9%), whilst the incomplete and partial MMIs were observed in 5.9% and 8.9%, respectively. The anterolateral infarctions (ALMIs) were very rare (2.9%). The complete and incomplete lateral infarctions (LMIs), noted in 35.3%, comprised 11.8% and 23.6%, respectively, that is, the anterior (5.9%), posterior (8.9%), deep (2.9%), and peripheral (5.9%). Dorsal ischemic lesions (DMIs) occurred in 11.8%, either as a complete (2.9%), or isolated lateral (5.9%) or medial infarctions (2.9%). The remaining ischemic regions belonged to various combined infarctions of the MMI, ALMI, LMI and DMI (35.3%). The infarctions most often affected the upper medulla (47.1%), middle (11.8%), or both (29.5%). Several motor and sensory signs were manifested following infarctions, including vestibular, cerebellar, ocular, sympathetic, respiratory and auditory symptoms.
CONCLUSIONS
There was a good correlation among the vascular territories, MRI ischemia features, and neurologic findings regarding the medullary infarctions.
Topics: Brain Stem Infarctions; Cerebellum; Formaldehyde; Humans; Magnetic Resonance Imaging; Medulla Oblongata
PubMed: 36029688
DOI: 10.1016/j.jstrokecerebrovasdis.2022.106730 -
Nature Oct 2015Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with...
Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation, and the neural circuits in the pons have since been studied extensively. The medulla also contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.
Topics: Animals; Eating; Female; GABAergic Neurons; Grooming; Male; Medulla Oblongata; Mice; Neural Pathways; Optogenetics; Periaqueductal Gray; Pons; Sleep, REM; Spinal Cord; Time Factors; Wakefulness; gamma-Aminobutyric Acid
PubMed: 26444238
DOI: 10.1038/nature14979 -
The Journal of Physiology Mar 2016We discuss recent evidence which suggests that the principal central respiratory chemoreceptors are located within the retrotrapezoid nucleus (RTN) and that RTN neurons... (Review)
Review
We discuss recent evidence which suggests that the principal central respiratory chemoreceptors are located within the retrotrapezoid nucleus (RTN) and that RTN neurons are directly sensitive to [H(+) ]. RTN neurons are glutamatergic. In vitro, their activation by [H(+) ] requires expression of a proton-activated G protein-coupled receptor (GPR4) and a proton-modulated potassium channel (TASK-2) whose transcripts are undetectable in astrocytes and the rest of the lower brainstem respiratory network. The pH response of RTN neurons is modulated by surrounding astrocytes but genetic deletion of RTN neurons or deletion of both GPR4 and TASK-2 virtually eliminates the central respiratory chemoreflex. Thus, although this reflex is regulated by innumerable brain pathways, it seems to operate predominantly by modulating the discharge rate of RTN neurons, and the activation of RTN neurons by hypercapnia may ultimately derive from their intrinsic pH sensitivity. RTN neurons increase lung ventilation by stimulating multiple aspects of breathing simultaneously. They stimulate breathing about equally during quiet wake and non-rapid eye movement (REM) sleep, and to a lesser degree during REM sleep. The activity of RTN neurons is regulated by inhibitory feedback and by excitatory inputs, notably from the carotid bodies. The latter input operates during normo- or hypercapnia but fails to activate RTN neurons under hypocapnic conditions. RTN inhibition probably limits the degree of hyperventilation produced by hypocapnic hypoxia. RTN neurons are also activated by inputs from serotonergic neurons and hypothalamic neurons. The absence of RTN neurons probably underlies the sleep apnoea and lack of chemoreflex that characterize congenital central hypoventilation syndrome.
Topics: Animals; Chemoreceptor Cells; Humans; Medulla Oblongata; Potassium Channels, Tandem Pore Domain; Protons; Receptors, G-Protein-Coupled; Reflex; Respiration; Sleep, REM
PubMed: 26748771
DOI: 10.1113/JP271480 -
ELife Jan 2023Obstructive sleep apnea (OSA) is characterized by sporadic collapse of the upper airway leading to periodic disruptions in breathing. Upper airway patency is governed by...
Obstructive sleep apnea (OSA) is characterized by sporadic collapse of the upper airway leading to periodic disruptions in breathing. Upper airway patency is governed by genioglossal nerve activity that originates from the hypoglossal motor nucleus. Mice with targeted deletion of the gene encoding the carbon monoxide (CO) producing enzyme, heme oxygenase-2 (HO-2), exhibit OSA, yet the contribution of central HO-2 dysregulation to the phenomenon is unknown. Using the rhythmic brainstem slice preparation that contains the preBötzinger complex (preBötC) and the hypoglossal nucleus, we tested the hypothesis that central HO-2 dysregulation weakens hypoglossal motoneuron output. Disrupting HO-2 activity increased the occurrence of subnetwork activity from the preBötC, which was associated with an increased irregularity of rhythmogenesis. These phenomena were also associated with the intermittent inability of the preBötC rhythm to drive output from the hypoglossal nucleus (i.e. transmission failures), and a reduction in the input-output relationship between the preBötC and the motor nucleus. HO-2 dysregulation reduced excitatory synaptic currents and intrinsic excitability in inspiratory hypoglossal neurons. Inhibiting activity of the CO-regulated HS producing enzyme, cystathionine-γ-lyase (CSE), reduced transmission failures in HO-2 null brainstem slices, which also normalized excitatory synaptic currents and intrinsic excitability of hypoglossal motoneurons. These findings demonstrate a hitherto uncharacterized modulation of hypoglossal activity through mutual interaction of HO-2/CO and CSE/HS, and support the potential importance of centrally derived gasotransmitter activity in regulating upper airway control.
Topics: Mice; Animals; Gasotransmitters; Motor Neurons; Respiration; Medulla Oblongata; Sleep Apnea, Obstructive; Hypoglossal Nerve
PubMed: 36656752
DOI: 10.7554/eLife.81978 -
Journal of Neurophysiology Jul 2022Cellular and network properties must be capable of generating rhythmic activity that is both flexible and stable. This is particularly important for breathing, a...
Cellular and network properties must be capable of generating rhythmic activity that is both flexible and stable. This is particularly important for breathing, a rhythmic behavior that dynamically adapts to environmental, behavioral, and metabolic changes from the first to the last breath. The pre-Bötzinger complex (preBötC), located within the ventral medulla, is responsible for producing rhythmic inspiration. Its cellular properties must be tunable, flexible as well as stabilizing. Here, we explore the role of the hyperpolarization-activated, nonselective cation current () for stabilizing PreBötC activity during opioid exposure and reduced excitatory synaptic transmission. Introducing into an in silico preBötC network predicts that loss of this depolarizing current should significantly slow the inspiratory rhythm. By contrast, in vitro and in vivo experiments revealed that the loss of minimally affected breathing frequency, but destabilized rhythmogenesis through the generation of incompletely synchronized bursts (burstlets). Associated with the loss of was an increased susceptibility of breathing to opioid-induced respiratory depression or weakened excitatory synaptic interactions, a paradoxical depolarization at the cellular level, and the suppression of tonic spiking. Tonic spiking activity is generated by nonrhythmic excitatory and inhibitory preBötC neurons, of which a large percentage express . Together, our results suggest that is important for maintaining tonic spiking, stabilizing inspiratory rhythmogenesis, and protecting breathing against perturbations or changes in network state. The current plays multiple roles within the preBötC. This current is important for promoting intrinsic tonic spiking activity in excitatory and inhibitory neurons and for preserving rhythmic function during conditions that dampen network excitability, such as in the context of opioid-induced respiratory depression. We therefore propose that the current expands the dynamic range of rhythmogenesis, buffers the preBötC against network perturbations, and stabilizes rhythmogenesis by preventing the generation of unsynchronized bursts.
Topics: Analgesics, Opioid; Humans; Medulla Oblongata; Neurons; Respiratory Center; Respiratory Insufficiency; Synaptic Transmission
PubMed: 35675444
DOI: 10.1152/jn.00150.2022 -
Journal of Neurophysiology May 2021Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the United States, the... (Review)
Review
Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the United States, the rate of death from opioid abuse since the early 1990s has grown disproportionally, prompting the classification as a nationwide "epidemic." Since this time, we have begun to unravel many fundamental cellular and systems-level mechanisms associated with opioid-related death. However, factors such as individual vulnerability, neuromodulatory compensation, and redundancy of opioid effects across central and peripheral nervous systems have created a barrier to a concise, integrative view of OIRD. Within this review, we bring together multiple perspectives in the field of OIRD to create an overarching viewpoint of what we know, and where we view this essential topic of research going forward into the future.
Topics: Analgesics, Opioid; Animals; Central Pattern Generators; Humans; Medulla Oblongata; Opioid-Related Disorders; Respiratory Insufficiency
PubMed: 33826874
DOI: 10.1152/jn.00017.2021 -
Cell Reports Jun 2022Motor control of the striated esophagus originates in the nucleus ambiguus (nAmb), a vagal motor nucleus that also contains upper airway motor neurons and...
Motor control of the striated esophagus originates in the nucleus ambiguus (nAmb), a vagal motor nucleus that also contains upper airway motor neurons and parasympathetic preganglionic neurons for the heart and lungs. We disambiguate nAmb neurons based on their genome-wide expression profiles, efferent circuitry, and ability to control esophageal muscles. Our single-cell RNA sequencing analysis predicts three molecularly distinct nAmb neuron subtypes and annotates them by subtype-specific marker genes: Crhr2, Vipr2, and Adcyap1. Mapping the axon projections of the nAmb neuron subtypes reveals that Crhr2 neurons innervate the esophagus, raising the possibility that they control esophageal muscle function. Accordingly, focal optogenetic stimulation of cholinergic Crhr2 fibers in the esophagus results in contractions. Activating Crhr2 neurons has no effect on heart rate, a key parasympathetic function of the nAmb, whereas activating all of the nAmb neurons robustly suppresses heart rate. Together, these results reveal a genetically defined circuit for motor control of the esophagus.
Topics: Heart Rate; Medulla Oblongata; Motor Neurons; Muscle, Smooth; Vagus Nerve
PubMed: 35705034
DOI: 10.1016/j.celrep.2022.110962 -
Scientific Reports Jun 2021Knowledge on the organization of motor function in the reticulospinal tract (RST) is limited by the lack of methods for measuring RST function in humans. Behavioral...
Knowledge on the organization of motor function in the reticulospinal tract (RST) is limited by the lack of methods for measuring RST function in humans. Behavioral studies suggest the involvement of the RST in long latency responses (LLRs). LLRs, elicited by precisely controlled perturbations, can therefore act as a viable paradigm to measure motor-related RST activity using functional Magnetic Resonance Imaging (fMRI). Here we present StretchfMRI, a novel technique developed to study RST function associated with LLRs. StretchfMRI combines robotic perturbations with electromyography and fMRI to simultaneously quantify muscular and neural activity during stretch-evoked LLRs without loss of reliability. Using StretchfMRI, we established the muscle-specific organization of LLR activity in the brainstem. The observed organization is partially consistent with animal models, with activity primarily in the ipsilateral medulla for flexors and in the contralateral pons for extensors, but also includes other areas, such as the midbrain and bilateral pontomedullary contributions.
Topics: Adult; Animals; Brain Stem; Cerebellum; Electromyography; Female; Humans; Magnetic Resonance Imaging; Male; Medulla Oblongata; Motor Cortex; Muscle, Skeletal; Neurons; Reaction Time; Spinal Cord; Young Adult
PubMed: 34131162
DOI: 10.1038/s41598-021-91605-5 -
Pulmonary Pharmacology & Therapeutics Dec 2015The dorsal medulla encompassing the nucleus of the tractus solitarius (NTS) and surrounding reticular formation (RF) has an important role in processing sensory... (Review)
Review
The dorsal medulla encompassing the nucleus of the tractus solitarius (NTS) and surrounding reticular formation (RF) has an important role in processing sensory information from the upper and lower airways for the generation and control of airway protective behaviors. These behaviors, such as cough and swallow, historically have been studied in isolation. However, recent information indicates that these and other airway protective behaviors are coordinated to minimize risk of aspiration. The dorsal medullary neural circuits that include the NTS are responsible for rhythmogenesis for repetitive swallowing, but previous models have assigned a role for this portion of the network for coughing that is restricted to monosynaptic sensory processing. We propose a more complex NTS/RF circuit that controls expression of swallowing and coughing and the coordination of these behaviors. The proposed circuit is supported by recordings of activity patterns of selected neural elements in vivo and simulations of a computational model of the brainstem circuit for breathing, coughing, and swallowing. This circuit includes separate rhythmic sub-circuits for all three behaviors. The revised NTS/RF circuit can account for the mode of action of antitussive drugs on the cough motor pattern, as well as the unique coordination of cough and swallow by a meta-behavioral control system for airway protection.
Topics: Animals; Cough; Deglutition; Humans; Medulla Oblongata; Neural Pathways; Neurogenesis; Respiratory System
PubMed: 26549786
DOI: 10.1016/j.pupt.2015.10.012