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Handbook of Clinical Neurology 2022Brain PCO is sensed primarily via changes in [H]. Small pH changes are detected in the medulla oblongata and trigger breathing adjustments that help maintain arterial... (Review)
Review
Brain PCO is sensed primarily via changes in [H]. Small pH changes are detected in the medulla oblongata and trigger breathing adjustments that help maintain arterial PCO constant. Larger perturbations of brain CO/H, possibly also sensed elsewhere in the CNS, elicit arousal, dyspnea, and stress, and cause additional breathing modifications. The retrotrapezoid nucleus (RTN), a rostral medullary cluster of glutamatergic neurons identified by coexpression of Phoxb and Nmb transcripts, is the lynchpin of the central respiratory chemoreflex. RTN regulates breathing frequency, inspiratory amplitude, and active expiration. It is exquisitely responsive to acidosis in vivo and maintains breathing autorhythmicity during quiet waking, slow-wave sleep, and anesthesia. The RTN response to [H] is partly an intrinsic neuronal property mediated by proton sensors TASK-2 and GPR4 and partly a paracrine effect mediated by astrocytes and the vasculature. The RTN also receives myriad excitatory or inhibitory synaptic inputs including from [H]-responsive neurons (e.g., serotonergic). RTN is silenced by moderate hypoxia. RTN inactivity (periodic or sustained) contributes to periodic breathing and, likely, to central sleep apnea. RTN development relies on transcription factors Egr2, Phox2b, Lbx1, and Atoh1. PHOX2B mutations cause congenital central hypoventilation syndrome; they impair RTN development and consequently the central respiratory chemoreflex.
Topics: Chemoreceptor Cells; Humans; Hypoxia; Medulla Oblongata; Respiration; Sleep Apnea, Central
PubMed: 35965033
DOI: 10.1016/B978-0-323-91534-2.00007-2 -
Journal of Clinical Neurophysiology :... Jan 1997We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of... (Review)
Review
We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.
Topics: Animals; Brain; Brain Mapping; Humans; Medulla Oblongata; Neurons; Nociceptors; Pain; Spinal Cord; Spinothalamic Tracts; Thalamus
PubMed: 9013357
DOI: 10.1097/00004691-199701000-00002 -
Nature Jun 2022The sympathetic and parasympathetic nervous systems regulate the activities of internal organs, but the molecular and functional diversity of their constituent neurons...
The sympathetic and parasympathetic nervous systems regulate the activities of internal organs, but the molecular and functional diversity of their constituent neurons and circuits remains largely unknown. Here we use retrograde neuronal tracing, single-cell RNA sequencing, optogenetics and physiological experiments to dissect the cardiac parasympathetic control circuit in mice. We show that cardiac-innervating neurons in the brainstem nucleus ambiguus (Amb) are comprised of two molecularly, anatomically and functionally distinct subtypes. The first, which we call ambiguus cardiovascular (ACV) neurons (approximately 35 neurons per Amb), define the classical cardiac parasympathetic circuit. They selectively innervate a subset of cardiac parasympathetic ganglion neurons and mediate the baroreceptor reflex, slowing heart rate and atrioventricular node conduction in response to increased blood pressure. The other, ambiguus cardiopulmonary (ACP) neurons (approximately 15 neurons per Amb) innervate cardiac ganglion neurons intermingled with and functionally indistinguishable from those innervated by ACV neurons. ACP neurons also innervate most or all lung parasympathetic ganglion neurons-clonal labelling shows that individual ACP neurons innervate both organs. ACP neurons mediate the dive reflex, the simultaneous bradycardia and bronchoconstriction that follows water immersion. Thus, parasympathetic control of the heart is organized into two parallel circuits, one that selectively controls cardiac function (ACV circuit) and another that coordinates cardiac and pulmonary function (ACP circuit). This new understanding of cardiac control has implications for treating cardiac and pulmonary diseases and for elucidating the control and coordination circuits of other organs.
Topics: Animals; Cardiovascular System; Heart; Lung; Medulla Oblongata; Mice; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Optogenetics; Parasympathetic Nervous System; RNA-Seq; Single-Cell Analysis
PubMed: 35650438
DOI: 10.1038/s41586-022-04760-8 -
International Journal of Molecular... Aug 2022The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric... (Review)
Review
The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric information. It is an evolutionarily highly conserved brain region, both structural and functional, and consists of a multitude of nuclei all involved in different aspects of basic but vital functions. Understanding the functional anatomy and developmental program of this structure can help elucidate potential role(s) of the medulla in neurological disorders. Here, we have described the early molecular patterning of the medulla during murine development, from the fundamental units that structure the very early medullary region into 5 rhombomeres (r7-r11) and 13 different longitudinal progenitor domains, to the neuronal clusters derived from these progenitors that ultimately make-up the different medullary nuclei. By doing so, we developed a schematic overview that can be used to predict the cell-fate of a progenitor group, or pinpoint the progenitor domain of origin of medullary nuclei. This schematic overview can further be used to help in the explanation of medulla-related symptoms of neurodevelopmental disorders, e.g., congenital central hypoventilation syndrome, Wold-Hirschhorn syndrome, Rett syndrome, and Pitt-Hopkins syndrome. Based on the genetic defects seen in these syndromes, we can use our model to predict which medullary nuclei might be affected, which can be used to quickly direct the research into these diseases to the likely affected nuclei.
Topics: Animals; Humans; Medulla Oblongata; Mice; Neurons; Rett Syndrome; Rhombencephalon; Spinal Cord
PubMed: 36012524
DOI: 10.3390/ijms23169260 -
Journal of Neurophysiology Mar 2021Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine,... (Review)
Review
Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO/H and regulate several aspects of breathing, including inspiration and active expiration.
Topics: Adenosine Triphosphate; Animals; Chemoreceptor Cells; Cholinergic Neurons; Humans; Medulla Oblongata; Receptors, Neurotransmitter; Receptors, Purinergic; Respiration; Respiratory Mechanics; Serotonergic Neurons
PubMed: 33427575
DOI: 10.1152/jn.00497.2020 -
Journal of Chemical Neuroanatomy Nov 2009This review focuses on presympathetic neurons in the medulla oblongata including the adrenergic cell groups C1-C3 in the rostral ventrolateral medulla and the... (Review)
Review
This review focuses on presympathetic neurons in the medulla oblongata including the adrenergic cell groups C1-C3 in the rostral ventrolateral medulla and the serotonergic, GABAergic and glycinergic neurons in the ventromedial medulla. The phenotypes of these neurons including colocalized neuropeptides (e.g., neuropeptide Y, enkephalin, thyrotropin-releasing hormone, substance P) as well as their relative anatomical location are considered in relation to predicting their function in control of sympathetic outflow, in particular the sympathetic outflows controlling blood pressure and thermoregulation. Several explanations are considered for how the neuroeffectors coexisting in these neurons might be functioning, although their exact purpose remains unknown. Although there is abundant data on potential neurotransmitters and neuropeptides contained in the presympathetic neurons, we are still unable to predict function and physiology based solely on the phenotype of these neurons.
Topics: Animals; Autonomic Pathways; Body Temperature Regulation; Cardiovascular Physiological Phenomena; Humans; Medulla Oblongata; Neurons; Neurotransmitter Agents; Reticular Formation; Sympathetic Nervous System
PubMed: 19665549
DOI: 10.1016/j.jchemneu.2009.07.005 -
Respiratory Physiology & Neurobiology Oct 2010An increase in PCO(2) in the arterial blood triggers immediate release of ATP from the ventral chemosensory site(s) on the surface of the medulla oblongata. Systemic... (Review)
Review
An increase in PCO(2) in the arterial blood triggers immediate release of ATP from the ventral chemosensory site(s) on the surface of the medulla oblongata. Systemic hypoxia in anesthetized rats was also associated with increased ATP release on the ventral medullary surface. During both hypoxia and hypercapnia, ATP and possibly other gliotransmitters released in the ventral medulla seemed to enhance cardiorespiratory responses to these stressors, and some of this ATP was proposed to be derived from astrocytes. Astrocytes also play a vital role controlling local blood flow. Astrocytes are activated by neurotransmitter release - especially glutamate and ATP. The astrocytic activation is manifest as a rise in intracellular Ca(2+) that is closely coupled to the metabolic activity of neurons in the active area. The activation of astrocytes spreads as a wave from astrocyte to astrocyte and causes release of ATP, adenosine, and other gliotransmitters that may alter neuronal function in the region of astrocytic activation. In addition, ATP, adenosine and other vasoactive substances, when released at the endfeet of astrocytes, interact with vascular receptors that may either dilate or constrict the vessels in the region closely adjacent to the site of neuronal activity. Thus, astrocytes seem to integrate neuronal metabolic needs by responding to the level of neuronal activity to regulate local blood flow and cardiorespiratory responses to hypoxia and hypercapnia to match substrate need (oxygen and glucose) with substrate availability and with the removal of CO(2). In so doing, astrocytes assume a larger role in information processing and in the regulation of neuronal activity and homeostasis of the entire organism than has been ascribed to them in the past.
Topics: Adenosine Triphosphate; Animals; Carbon Dioxide; Cerebrovascular Circulation; Chemoreceptor Cells; Humans; Medulla Oblongata; Neuroglia; Neurons; Respiratory Physiological Phenomena
PubMed: 20601205
DOI: 10.1016/j.resp.2010.06.009 -
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 -
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 -
Nature Communications Feb 2023Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing is also modified by behavior and emotion. Mice have rapid...
Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing is also modified by behavior and emotion. Mice have rapid breathing patterns that are unique to the awake state and distinct from those driven by automatic reflexes. Activation of medullary neurons that control automatic breathing does not reproduce these rapid breathing patterns. By manipulating transcriptionally defined neurons in the parabrachial nucleus, we identify a subset of neurons that express the Tac1, but not Calca, gene that exerts potent and precise conditional control of breathing in the awake, but not anesthetized, state via projections to the ventral intermediate reticular zone of the medulla. Activating these neurons drives breathing to frequencies that match the physiological maximum through mechanisms that differ from those that underlie the automatic control of breathing. We postulate that this circuit is important for the integration of breathing with state-dependent behaviors and emotions.
Topics: Mice; Animals; Neurons; Respiration; Medulla Oblongata
PubMed: 36810601
DOI: 10.1038/s41467-023-36603-z