scholarly journals Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease

2021 ◽  
Author(s):  
Geidy E. Serrano ◽  
Jessica E. Walker ◽  
Richard Arce ◽  
Michael J. Glass ◽  
Daisy Vargas ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Area Postrema ◽  
Brain Regions ◽  
Motor Nucleus ◽  
Brain Invasion ◽  
Dorsal Motor Nucleus ◽  
Age Related ◽  
The Subject ◽  
Human Coronaviruses ◽  
Acute Cerebral Infarct

ABSTRACTThe coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal β-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.

scholarly journals Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

2019 ◽  
Author(s):  
Alastair J. MacDonald ◽  
Fiona E. Holmes ◽  
Craig Beall ◽  
Anthony E. Pickering ◽  
Kate L.J. Ellacott
Keyword(s):  
Food Intake ◽  
Area Postrema ◽  
Active Role ◽  
Brain Regions ◽  
Negative Energy ◽  
Motor Nucleus ◽  
Dorsal Vagal Complex ◽  
Structural Support ◽  
Dorsal Motor Nucleus ◽  
Hypothalamic Arcuate Nucleus

Food intake is controlled by the coordinated action of numerous brain regions but a complete understanding remains elusive. Of these brain regions the brainstem dorsal vagal complex (DVC) is the first site for integration of visceral synaptic and hormonal cues that act to inhibit food intake. The DVC consists of three nuclei: the nucleus of the solitary tract (NTS), area postrema (AP) and dorsal motor nucleus of the vagus (DMX). Targeted chemogenetic activation of appetite-responsive NTS neuronal populations causes short term decreases in food intake. Astrocytes are a class of glial cell which provide metabolic and structural support to neurons and play an active role in modulating neurotransmission. Within the hypothalamic arcuate nucleus (ARC) astrocytes are regulated by both positive and negative energy balance and express receptors for hormones that influence satiety and hunger. Chemogenetic activation of these ARC astrocytes alters food intake. Since NTS astrocytes respond to vagal stimulation, we hypothesised that they may be involved in mediating satiety. Here we show that NTS astrocytes show plastic alterations in morphology following excess food consumption and that chemogenetic activation of DVC astrocytes causes a decrease in food intake, by recruiting an appetite-inhibiting circuit, without producing aversion. These findings are the first using genetically-targeted manipulation of DVC astrocytes to demonstrate their role in the brain’s regulation of food intake.

Studies of the Central Neural Pathways to the Stomach and Zusanli (ST36)

2001 ◽  
Vol 29 (02) ◽  
pp. 211-220 ◽  
Author(s):  
Chang Hyun Lee ◽  
Han Sol Jung ◽  
Tae Young Lee ◽  
Sang Ryoung Lee ◽  
Sang Won Yuk ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Vagus Nerve ◽  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Reticular Nucleus ◽  
Hypothalamic Nucleus ◽  
Cell Group ◽  
Motor Nucleus ◽  
Amygdaloid Nucleus ◽  
Dorsal Motor Nucleus

The purpose of this morphological study was to investigate the relation between the meridian, meridian points and viscera using neuroanatomical tracers. The common locations of the spinal cord and brain projecting to the stomach and Zusanli were observed following injection of CTB (cholera toxin B subunit) and pseudorabies viruses (PRV-Ba, Bartha strain and PRV-Ba-Gal, galactosidase insertion) into the stomach and Zusanli (ST36). After 4–5 days of survival following injection into twelve rats, they were perfused, and their spinal cords and brains were frozen sectioned (30 μm). These sections were stained by X-gal histochemical, CTB and PRV-Bia immunohistochemical staining methods, and examined with the light microscope. The results were as follows: Commonly labeled medulla oblongata regions were dorsal motor nucleus of vagus nerve (DMV), nucleus tractus solitarius (NTS) and area postrema (AP) following injection of CTB and PRV-Ba-Gal into stomach and Zusanli, respectively. In the spinal cord, commonly labeled neurons were found in thoracic, lumbar and sacral spinal segments. Densely labeled areas were found in lamina IV, V, VII (intermediolateral nucleus) and X of the spinal cord. In the brain, commonly labeled neurons were found in the A1 noradrenalin cells/C1 adrenalin cells/caudoventrolateral reticular nucleus, dorsal motor nucleus of vagus nerve, nucleus tractus solitarius, area postrema, raphe obscurus nucleus, raphe pallidus nucleus, raphe magnus nucleus, gigantocellular nucleus, locus coeruleus, parabrachial nucleus, Kolliker-Fuse nucleus, A5 cell group, central gray matter, paraventricular hypothalamic nucleus, lateral hypothalamic nucleus, retrochiasmatic hypothalamic nucleus, bed nucleus of stria terminals and amygdaloid nucleus. Thus central autonomic center project both to the stomach and Zusanli. These morphological results suggest that there is a commonality of CNS cell groups in brain controlling stomach (viscera) and Zusanli (limb).

scholarly journals Input-output signal processing plasticity of vagal motorneurons in response to cardiac ischemic injury

2020 ◽  
Author(s):  
Jonathan Gorky ◽  
Alison Moss ◽  
Marina Balycheva ◽  
Rajanikanth Vadigepalli ◽  
James S. Schwaber
Keyword(s):  
Signal Processing ◽  
Output Signal ◽  
Ischemic Injury ◽  
Brain Regions ◽  
Therapeutic Interventions ◽  
Motor Nucleus ◽  
Input Output ◽  
Dorsal Motor Nucleus ◽  
Transcriptomics Data ◽  
Dramatic Shift

AbstractVagal stimulation is emerging as the next frontier in bioelectronic medicine to modulate peripheral organ health and treat disease. The neuronal molecular phenotypes in the dorsal motor nucleus of the vagus (DMV) remain largely unexplored, limiting the potential for harnessing the DMV plasticity for therapeutic interventions. We developed a mesoscale single cell transcriptomics data from hundreds of DMV neurons under homeostasis and following physiological perturbations. Our results revealed that homeostatic DMV neuronal states can be organized into distinguishable input-output signal processing units. Remote ischemic preconditioning induced a distinctive shift in the neuronal states towards diminishing the role of inhibitory inputs, with concomitant changes in regulatory microRNAs miR-218a and miR-495. Chronic cardiac ischemic injury resulted in a dramatic shift in DMV neuronal states suggestive of enhanced neurosecretory function. We propose a DMV molecular network mechanism that integrates combinatorial neurotransmitter inputs from multiple brain regions and humoral signals to modulate cardiac health.

Cardiovascular responses to microinjection of ANF into dorsal medulla of rats

1988 ◽  
Vol 255 (1) ◽  
pp. R182-R187 ◽  
Author(s):  
D. J. McKitrick ◽  
F. R. Calaresu
Keyword(s):  
Area Postrema ◽  
Cardiovascular Responses ◽  
Significant Decline ◽  
Medial Longitudinal Fasciculus ◽  
Hypoglossal Nucleus ◽  
Cardiovascular Reflexes ◽  
Motor Nucleus ◽  
Cuneate Nucleus ◽  
Dorsal Motor Nucleus ◽  
Dorsal Medulla

Atrial natriuretic factor (ANF) has been suggested as a putative neurotransmitter in central pathways involved in the control of the cardiovascular system. To investigate this possibility, 50 nl of 10(-7) M ANF were microinjected into discrete sites in the nucleus of the tractus solitarius (NTS) where baro- and chemoreceptor afferents terminate. Injections into 36 of a total of 66 sites in the NTS of paralyzed artificially ventilated Wistar rats under urethan anesthesia were found to produce a significant decline in heart rate [HR; -9.2 +/- 2.9 (SE) beats/min, P less than 0.05] and mean arterial pressure [MAP; -11.1 +/- 1.2 (SE) mmHg, P less than 0.01]. Similar responses were also present in anesthetized animals breathing spontaneously. Microinjection of an inactive peptide analogue or of saline did not produce cardiovascular changes. It was also found that ANF injection into the cuneate nucleus (20 of 38 sites) and the spinal trigeminal complex (28 of 42 sites) produced a decrease in MAP and HR that were of the same magnitude as those seen in the NTS. Injections of ANF into the medial longitudinal fasciculus (n = 22), hypoglossal nucleus (n = 9), area postrema (n = 16), and dorsal motor nucleus of the vagus (n = 11) did not change HR or MAP. These results suggest that ANF may serve as a neurotransmitter involved in cardiovascular reflexes mediated by specific nuclei in the dorsal medulla.

Δ9-Tetrahydrocannabinol selectively acts on CB1 receptors in specific regions of dorsal vagal complex to inhibit emesis in ferrets

2003 ◽  
Vol 285 (3) ◽  
pp. G566-G576 ◽  
Author(s):  
Marja D. Van Sickle ◽  
Lorraine D. Oland ◽  
Ken Mackie ◽  
Joseph S. Davison ◽  
Keith A. Sharkey
Keyword(s):  
Receptor Antagonist ◽  
Brain Stem ◽  
Area Postrema ◽  
Motor Nucleus ◽  
Cb1 Receptors ◽  
Dorsal Vagal Complex ◽  
Dorsal Motor Nucleus ◽  
Site Of Action ◽  
Fos Expression ◽  
The Brain

The aim of this study was to investigate the efficacy, receptor specificity, and site of action of Δ9-tetrahydrocannabinol (THC) as an antiemetic in the ferret. THC (0.05-1 mg/kg ip) dose-dependently inhibited the emetic actions of cisplatin. The ED50 for retching was ∼0.1 mg/kg and for vomiting was 0.05 mg/kg. A specific cannabinoid (CB)1 receptor antagonist SR-141716A (5 mg/kg ip) reversed the effect of THC, whereas the CB2 receptor antagonist SR-144528 (5 mg/kg ip) was ineffective. THC applied to the surface of the brain stem was sufficient to inhibit emesis induced by intragastric hypertonic saline. The site of action of THC in the brain stem was further assessed using Fos immunohistochemistry. Fos expression induced by cisplatin in the dorsal motor nucleus of the vagus (DMNX) and the medial subnucleus of the nucleus of the solitary tract (NTS), but not other subnuclei of the NTS, was significantly reduced by THC rostral to obex. At the level of the obex, THC reduced Fos expression in the area postrema and the dorsal subnucleus of the NTS. The highest density of CB1 receptor immunoreactivity was found in the DMNX and the medial subnucleus of the NTS. Lower densities were observed in the area postrema and dorsal subnucleus of the NTS. Caudal to obex, there was moderate density of staining in the commissural subnucleus of the NTS. These results show that THC selectively acts at CB1 receptors to reduce neuronal activation in response to emetic stimuli in specific regions of the dorsal vagal complex.

scholarly journals Effect of brain stem NMDA-receptor blockade by MK-801 on behavioral and Fos responses to vagal satiety signals

1999 ◽  
Vol 277 (4) ◽  
pp. R1104-R1111 ◽  
Author(s):  
Huiyuan Zheng ◽  
Lisa Kelly ◽  
Laurel M. Patterson ◽  
Hans-Rudolf Berthoud
Keyword(s):  
Nmda Receptor ◽  
Area Postrema ◽  
Additive Model ◽  
Nmda Receptor Antagonist ◽  
Gastric Distension ◽  
Motor Nucleus ◽  
Sucrose Intake ◽  
Mk 801 ◽  
Dorsal Motor Nucleus ◽  
Fos Expression

To test the possible role of N-methyl-d-aspartate (NMDA) glutamate receptors in the transmission of gastrointestinal satiety signals at the level of the nucleus of the solitary tract (NTS), we assessed the effect of fourth ventricular infusion of the noncompetitive NMDA receptor antagonist MK-801 on short-term sucrose intake and on gastric distension-induced Fos expression in the dorsal vagal complex of unanesthetized rats. MK-801, although not affecting initial rate of intake, significantly increased sucrose intake during the later phase of the meal (10–30 min, 8.9 ± 1.0 vs. 2.9 ± 0.8 ml, P < 0.01). In the medial subnucleus of the NTS, the area postrema, and the dorsal motor nucleus, MK-801 did not reduce gastric distension-induced Fos expression and itself did not significantly induce Fos expression. In the dorsomedial, commissural, and gelatinosus subnuclei, MK-801 in itself produced significant Fos expression and significantly reduced (−75%, P < 0.05) the ability of gastric distension to induce Fos expression, assuming an additive model with two separate populations of neurons activated by distension and the blocker. Although these results are consistent with NMDA receptor-mediated glutamatergic transmission of vagal satiety signals in general, they lend limited support for such a role in the transmission of specific gastric distension signals.

Oral-pharyngeal-esophageal and gastric cues contribute to meal-induced c-fos expression

1995 ◽  
Vol 268 (1) ◽  
pp. R223-R230 ◽  
Author(s):  
K. A. Fraser ◽  
E. Raizada ◽  
J. S. Davison
Keyword(s):  
Area Postrema ◽  
Receptor Activation ◽  
Gastric Distension ◽  
Motor Nucleus ◽  
Gastric Fistula ◽  
Gastric Balloon ◽  
Sham Feeding ◽  
Dorsal Motor Nucleus ◽  
Caudal Level

We recently demonstrated that a meal induces c-fos immunoreactivity in the dorsal motor nucleus of the vagus (DMV), the nucleus of the tractus solitarius (NTS), and the area postrema (AP) of the rat brain stem. This response was not eliminated by the cholecystokinin A (CCK-A) antagonist L-364,718, a finding suggesting that feeding induces c-fos immunoreactivity by a pathway that is largely independent of CCK-A receptor activation. Consequently, the role of alternative gastrointestinal cues in the induction of c-fos was investigated. The induction of c-fos after oral-pharyngeal and esophageal stimuli was examined by use of a sham-feeding procedure via a gastric fistula. Gastric fistula-closed and fed rats displayed c-fos immunoreactivity similar to that of meal-fed rats seen previously. Fistula-open and fed rats showed the same degree of staining in the more rostral section of NTS examined as fistula-closed and fed rats, but fewer c-fos-positive nuclei in the more caudal level of the NTS. The potential for gastric distension to induce c-fos was assessed after the inflation of a gastric balloon. Physiological inflation of the balloon produced marked c-fos induction primarily in the medial NTS.

Ghrelin acts on the dorsal vagal complex to stimulate pancreatic protein secretion

2006 ◽  
Vol 290 (6) ◽  
pp. G1350-G1358 ◽  
Author(s):  
Ying Li ◽  
Xiaoyin Wu ◽  
Ying Zhao ◽  
Shengliang Chen ◽  
Chung Owyang
Keyword(s):  
Brain Stem ◽  
Protein Secretion ◽  
Intravenous Infusion ◽  
Pancreatic Secretion ◽  
Area Postrema ◽  
Fold Increase ◽  
Motor Nucleus ◽  
Dorsal Motor Nucleus ◽  
Selective Ablation

Ghrelin receptors are present in the central nervous system. We hypothesized that ghrelin released from the stomach acts as an endocrine substance and stimulates brain stem vagovagal circuitry to evoke pancreatic secretion. In an in vivo anesthetized rat model, an intravenous infusion of ghrelin at doses of 5, 10, and 25 nmol increased pancreatic protein secretion from a basal level of 125 ± 6 to 186 ± 8, 295 ± 12, and 356 ± 11 mg/h, respectively. Pretreatment with atropine or hexamethonium or an acute vagotomy, but not a perivagal application of capsaicin, completely abolished pancreatic protein secretion responses to ghrelin. In conscious rats, an intravenous infusion of ghrelin at a dose of 10 nmol resulted in a 2.2-fold increase in pancreatic protein secretion over basal volume. Selective ablation of the area postrema abolished pancreatic protein secretion stimulated by intravenous infusion of ghrelin but did not alter the increase in pancreatic protein secretion evoked by diversion of bile-pancreatic juice. Immunohistochemical staining showed a marked increase in the number of c-Fos-expressing neurons in the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus after an intravenous infusion of ghrelin in sham-lesioned rats; selective ablation of the area postrema eliminated this increase. In conclusion, ghrelin stimulates pancreatic secretion via a vagal cholinergic efferent pathway. Circulating ghrelin gains access to the brain stem vagovagal circuitry via the area postrema, which represents the primary target on which peripheral ghrelin may act as an endocrine substance to stimulate pancreatic secretion.

Hypothyroidism increases Fos immunoreactivity in cholinergic neurons of brain medullary dorsal vagal complex in rats

2005 ◽  
Vol 289 (5) ◽  
pp. E892-E899 ◽  
Author(s):  
Pu-Qing Yuan ◽  
Hong Yang
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Area Postrema ◽  
Tap Water ◽  
Cholinergic Neurons ◽  
Thyroid Hormone Receptors ◽  
Motor Nucleus ◽  
Dorsal Motor Nucleus ◽  
Fos Expression ◽  
Daily Intraperitoneal Injection

Hypo- or hyperthyroidism is associated with autonomic disorders. We studied Fos expression in the medullary dorsal motor nucleus of the vagus (DMV), nucleus tractus solitarii (NTS), and area postrema (AP) in four groups of rats with different thyroid states induced by a combination of drinking water and daily intraperitoneal injection for 1–4 wk: 1) tap water and vehicle; 2) 0.1% propylthiouracil (PTU) and vehicle; 3) PTU and thyroxine (T4; 2 μg/100 g); and 4) tap water and T4 (10 μg/100 g). The numbers of Fos immunoreactive (IR) positive neurons in the DMV, NTS, and AP were low in euthyroid rats but significantly higher in the 4-wk duration in hypothyroid rats, which were prevented by simultaneous T4 replacement. Hyperthyroidism had no effect on Fos expression in these areas. There were significant negative correlations between T4 levels and the numbers of Fos-IR-positive neurons in the DMV ( r = −0.6388, P < 0.008), NTS ( r = −0.6741, P < 0.003), and AP ( r = −0.5622, P < 0.004). Double staining showed that Fos immunoreactivity in the DMV of hypothyroid rats was mostly localized in choline acetyltransferase-containing neurons. Thyroid hormone receptors α1 and β2 were localized in the observed nuclei. These results indicate that thyroid hormone influences the DMV/NTS/AP neuronal activity, which may contribute to the vagal-related visceral disorders observed in hypothyroidism.

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