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Journal of Neurophysiology Aug 2016The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as... (Review)
Review
The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as central respiratory chemoreceptors, i.e., the mechanism by which brain Pco2 regulates breathing. The molecular and cellular basis of central respiratory chemoreception is based on the detection of CO2 via intrinsic proton receptors (TASK-2, GPR4) as well as synaptic input from peripheral chemoreceptors and other brain regions. Murine models of congenital central hypoventilation syndrome designed with PHOX2B mutations have suggested RTN neuron agenesis. In this review, we examine, through human and experimental animal models, how a restricted number of neurons that express the transcription factor PHOX2B play a crucial role in the control of breathing and autonomic regulation.
Topics: Animals; Autonomic Nervous System Diseases; Chemoreceptor Cells; Disease Models, Animal; Homeodomain Proteins; Humans; Hypoventilation; Medulla Oblongata; Respiration Disorders; Sleep Apnea, Central; Transcription Factors
PubMed: 27226447
DOI: 10.1152/jn.00026.2016 -
The Journal of Neuroscience : the... Mar 2017Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous...
Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity ( < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task × temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands. Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia.
Topics: Adolescent; Adult; Analgesia; Analysis of Variance; Attention; Body Temperature; Brain Mapping; Brain Stem; Female; Humans; Image Processing, Computer-Assisted; Locus Coeruleus; Magnetic Resonance Imaging; Male; Medulla Oblongata; Middle Aged; Neural Pathways; Pain Measurement; Photic Stimulation; Young Adult
PubMed: 28096471
DOI: 10.1523/JNEUROSCI.2193-16.2016 -
Neurological Sciences : Official... Nov 2022Lateral medullary syndrome (LMS) is an ischemic stroke of the medulla oblongata that involves the territory of the posterior inferior cerebellar artery. LMS is often...
Lateral medullary syndrome (LMS) is an ischemic stroke of the medulla oblongata that involves the territory of the posterior inferior cerebellar artery. LMS is often missed as the cause of autonomic dysregulation in patients with recent brain stem stroke. Due to the location of the nucleus tractus solitarius (NTS), the dorsal vagal nucleus, and the nucleus ambiguous in the lateral medulla oblongata, patients with LMS occasionally have autonomic dysregulation-associated clinical manifestations. We report a case of LMS-associated autonomic dysregulation. The case presented by recurrent syncope, requiring permanent pacemaker placement. This case shows the importance of recognizing LMS as a potential cause of life-threatening arrhythmias, heart block, and symptomatic bradycardia. Extended cardiac monitoring should be considered for patients with medullary strokes.
Topics: Humans; Medulla Oblongata; Lateral Medullary Syndrome; Infarction
PubMed: 35925455
DOI: 10.1007/s10072-022-06306-2 -
Journal of Neuropathology and... May 2023The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period....
Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits.
The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g. altered serotonin (5-HT)1A receptor binding), in SIDS cases. In rodents, 5-HT2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. Nonetheless, the role of 5-HT2A/C receptors in the pathophysiology of SIDS is unclear. We hypothesize that in SIDS, 5-HT2A/C receptor binding is altered in medullary nuclei that are key for arousal and autoresuscitation. Here, we report altered 5-HT2A/C binding in several key medullary nuclei in SIDS cases (n = 58) compared to controls (n = 12). In some nuclei the reduced 5-HT2A/C and 5-HT1A binding overlapped, suggesting abnormal 5-HT receptor interactions. The data presented here (Part 1) suggest that a subset of SIDS is due in part to abnormal 5-HT2A/C and 5-HT1A signaling across multiple medullary nuclei vital for arousal and autoresuscitation. In Part II to follow, we highlight 8 medullary subnetworks with altered 5-HT receptor binding in SIDS. We propose the existence of an integrative brainstem network that fails to facilitate arousal and/or autoresuscitation in SIDS cases.
Topics: Humans; Sudden Infant Death; Brain Stem; Arousal; Brain; Medulla Oblongata
PubMed: 37226597
DOI: 10.1093/jnen/nlad030 -
ELife Oct 2022Regulation of systemic PCO is a life-preserving homeostatic mechanism. In the medulla oblongata, the retrotrapezoid nucleus (RTN) and rostral medullary Raphe are...
Regulation of systemic PCO is a life-preserving homeostatic mechanism. In the medulla oblongata, the retrotrapezoid nucleus (RTN) and rostral medullary Raphe are proposed as CO chemosensory nuclei mediating adaptive respiratory changes. Hypercapnia also induces active expiration, an adaptive change thought to be controlled by the lateral parafacial region (pF). Here, we use GCaMP6 expression and head-mounted mini-microscopes to image Ca activity in these nuclei in awake adult mice during hypercapnia. Activity in the pF supports its role as a homogenous neuronal population that drives active expiration. Our data show that chemosensory responses in the RTN and Raphe differ in their temporal characteristics and sensitivity to CO, raising the possibility these nuclei act in a coordinated way to generate adaptive ventilatory responses to hypercapnia. Our analysis revises the understanding of chemosensory control in awake adult mouse and paves the way to understanding how breathing is coordinated with complex non-ventilatory behaviours.
Topics: Mice; Animals; Hypercapnia; Carbon Dioxide; Medulla Oblongata; Brain Stem; Respiration
PubMed: 36300918
DOI: 10.7554/eLife.70671 -
American Journal of Physiology.... Jul 2019Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn...
Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn the control of breathing. IL-10 knockout mice (IL-10, = 10) and wild-type mice (IL-10, = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO-93% O, normoxic hypercapnia 7% CO-21% O, hypoxic hypercapnia 7% CO-10% O, and hypoxic normocapnia 3% CO-10% O. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 μg/kg) was administered intraperitoneally to wild-type mice ( = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10-30 ng/ml, = 8). We found that IL-10 mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10 mice during room air breathing and in all test gases (by 23.62 to 33.2%, < 0.05 and -36.23 to -41.69%, < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10 mice was lower than IL-10 (by -15.67 to -22.74%, < 0.05). The rapid shallow breathing index was higher in IL-10 mice compared with IL-10 mice in all inspired gases (by 50.25 to 57.5%, < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by -12.22 to -29.53 and 32.18 to 45.11%, < 0.05, respectively). IL-10 administration in neonatal rat ( = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing.
Topics: Animals; Brain; Carbon Dioxide; Gene Expression Regulation; Interleukin-10; Male; Medulla Oblongata; Mice; Mice, Knockout; Oxygen; Respiratory Physiological Phenomena
PubMed: 31091151
DOI: 10.1152/ajpregu.00065.2019 -
Veterinary Pathology Jan 2023This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of...
This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.
Topics: Animals; Swine; Female; Pantothenic Acid; Spinal Cord; Neurons; Medulla Oblongata; Spinal Cord Diseases; Swine Diseases
PubMed: 36250539
DOI: 10.1177/03009858221128920 -
Physiology & Behavior Sep 2019Glucose is the required metabolic substrate for the brain. Yet the brain stores very little glucose. Therefore, the brain continuously monitors glucose availability to... (Review)
Review
Glucose is the required metabolic substrate for the brain. Yet the brain stores very little glucose. Therefore, the brain continuously monitors glucose availability to detect hypoglycemia and to mobilize system-wide responses to protect and restore euglycemia. Catecholamine (CA) neurons in the hindbrain are critical elements of the brain's glucoregulatory mechanisms. They project widely throughout the brain and spinal cord, innervating sites controlling behavioral, endocrine and visceral responses. Hence, CA neurons are capable of triggering a rapid, coordinated and multifaceted response to glucose challenge. This article reviews experimental data that has begun to elucidate the importance of CA neurons for glucoregulation, the functions of specific CA subpopulations in the ventrolateral medulla, and the extended circuitry through which they engage other levels of the nervous system to accomplish their essential glucoregulatory task. Hopefully, this review also suggests the vast amount of work yet to be done in this area and the justification for engaging in that effort.
Topics: Animals; Glucose; Medulla Oblongata; Neurons; Rhombencephalon
PubMed: 31173784
DOI: 10.1016/j.physbeh.2019.112568 -
The Journal of Physiology Mar 2015The rostral ventrolateral medulla oblongata (RVLM) contains two functionally distinct types of neurons that control and orchestrate cardiovascular and respiratory... (Review)
Review
The rostral ventrolateral medulla oblongata (RVLM) contains two functionally distinct types of neurons that control and orchestrate cardiovascular and respiratory responses to hypoxia and hypercapnia. One group is composed of the central chemoreceptor neurons of the retrotrapezoid nucleus, which provides a CO₂/H(+) -dependent drive to breathe and serves as an integration centre and a point of convergence of chemosensory information from other central and peripheral sites, including the carotid bodies. The second cluster of RVLM cells forms a population of neurons belonging to the C1 catecholaminergic group that controls sympathetic vasomotor tone in resting conditions and in conditions of hypoxia and hypercapnia. Recent evidence suggests that ATP-mediated purinergic signalling at the level of the RVLM co-ordinates cardiovascular and respiratory responses triggered by hypoxia and hypercapnia by activating retrotrapezoid nucleus and C1 neurons, respectively. The role of ATP-mediated signalling in the RVLM mechanisms of cardiovascular and respiratory activities is the main subject of this short review.
Topics: Animals; Carbon Dioxide; Chemoreceptor Cells; Humans; Medulla Oblongata; Receptors, Purinergic; Sympathetic Nervous System
PubMed: 25524282
DOI: 10.1113/jphysiol.2014.284430 -
The Journal of Neuroscience : the... Nov 2017The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial...
The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial region of the medulla oblongata. An unknown proportion of RTN neurons are central respiratory chemoreceptors and there is mounting evidence for biochemical diversity among these cells. Here, we used multiplexed hybridization and single-cell RNA-Seq in male and female mice to provide a more comprehensive view of the phenotypic diversity of RTN neurons. We now demonstrate that the RTN of mice can be identified with a single and specific marker, mRNA (). Most (∼75%) RTN neurons express low-to-moderate levels of and display chemoreceptor properties. Namely they are activated by hypercapnia, but not by hypoxia, and express proton sensors, TASK-2 and Gpr4. These -low RTN neurons also express varying levels of transcripts for , , and , and receptors for substance P, orexin, serotonin, and ATP. A subset of RTN neurons (∼20-25%), typically larger than average, express very high levels of mRNA. These -high RTN neurons do not express after hypercapnia and have low-to-undetectable levels of or transcripts; they also express , but are essentially devoid of and transcripts. In male rats, is also a marker of the RTN but, unlike in mice, this gene is expressed by other types of nearby neurons located within the ventromedial medulla. In sum, is a selective marker of the RTN in rodents; -low neurons, the vast majority, are central respiratory chemoreceptors, whereas -high neurons likely have other functions. Central respiratory chemoreceptors regulate arterial PCO by adjusting lung ventilation. Such cells have recently been identified within the retrotrapezoid nucleus (RTN), a brainstem nucleus defined by genetic lineage and a cumbersome combination of markers. Using single-cell RNA-Seq and multiplexed hybridization, we show here that a single marker, mRNA (), identifies RTN neurons in rodents. We also suggest that >75% of these neurons are chemoreceptors because they are strongly activated by hypercapnia and express high levels of proton sensors ( and ). The other RTN neurons express very high levels of , but low levels of , and do not respond to hypercapnia. Their function is unknown.
Topics: Animals; Female; Gene Expression; Hypoxia; Male; Medulla Oblongata; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurokinin B; Neurons; Organ Culture Techniques; Rats; Rats, Sprague-Dawley
PubMed: 29066557
DOI: 10.1523/JNEUROSCI.2055-17.2017