scholarly journals Olfactory Bulb and Amygdala Gene Expression Changes in Subjects Dying with COVID-19

2021 ◽  
Author(s):  
Ignazio S Piras ◽  
Matt Huentelman ◽  
Jessica Walker ◽  
Richard Arche ◽  
Michael Glass ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Viral Entry ◽  
Brain Regions ◽  
Cns Infection ◽  
Compensatory Response ◽  
Neuronal Genes ◽  
Transcriptional Changes ◽  
Key Genes ◽  
Neurological Effects ◽  
The Brain

In this study we conducted RNA sequencing on two brain regions (olfactory bulb and amygdala) from subjects who died from COVID-19 or who died of other causes. We found several-fold more transcriptional changes in the olfactory bulb than in the amygdala, consistent with our own work and that of others indicating that the olfactory bulb may be the initial and most common brain region infected. To some extent our results converge with pseudotime analysis towards common processes shared between the brain regions, possibly induced by the systemic immune reaction following SARS-CoV-2 infection. Changes in amygdala emphasized upregulation of interferon-related neuroinflammation genes, as well as downregulation of synaptic and other neuronal genes, and may represent the substrate of reported acute and subacute COVID-19 neurological effects. Additionally, and only in olfactory bulb, we observed an increase in angiogenesis and platelet activation genes, possibly associated with microvascular damages induced by neuroinflammation. Through coexpression analysis we identified two key genes (CAMK2B for the synaptic neuronal network and COL1A2 for the angiogenesis/platelet network) that might be interesting potential targets to reverse the effects induced by SARS-CoV-2 infection. Finally, in olfactory bulb we detected an upregulation of olfactory and taste genes, possibly as a compensatory response to functional deafferentation caused by viral entry into primary olfactory sensory neurons. In conclusion, we were able to identify transcriptional profiles and key genes involved in neuroinflammation, neuronal reaction and olfaction induced by direct CNS infection and/or the systemic immune response to SARS-CoV-2 infection.

scholarly journals Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions during Toxoplasma gondii infection

2019 ◽  
Vol 116 (49) ◽  
pp. 24796-24807 ◽  
Author(s):  
Christine A. Schneider ◽  
Dario X. Figueroa Velez ◽  
Ricardo Azevedo ◽  
Evelyn M. Hoover ◽  
Cuong J. Tran ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Light Sheet ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cell Segmentation ◽  
Cns Infection ◽  
Light Sheet Microscopy ◽  
Blood Brain ◽  
The Brain

Brain infection by the parasite Toxoplasma gondii in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling T. gondii. However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2+Ly6Chi) and patrolling (CX3CR1+Ly6Clo) monocytes into the blood and brain during T. gondii infection of C57BL/6J and CCR2RFP/+CX3CR1GFP/+ mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood–brain barrier (BBB) within 2 wk of T. gondii infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact T. gondii-infected brains using iDISCO+ and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of T. gondii and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of T. gondii clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., Nature 445:168–176 (2007)] indicated a consistent pattern of monocyte infiltration during T. gondii infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during T. gondii CNS infection.

scholarly journals The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation

2020 ◽  
Author(s):  
Elizabeth M. Rhea ◽  
Aric F. Logsdon ◽  
Kim M. Hansen ◽  
Lindsey Williams ◽  
May Reed ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Blood Brain Barrier ◽  
Apoe Genotype ◽  
Brain Regions ◽  
Brain Barrier ◽  
Productive Infection ◽  
Peripheral Tissues ◽  
Blood Brain ◽  
Commercial Sources ◽  
The Brain

AbstractEvidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 ± 0.024 μL/g-min and 0.294 ± 0.032 μL/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10th the amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis.Graphical Abstract

scholarly journals Interactions of SARS-CoV-2 with the Blood–Brain Barrier

2021 ◽  
Vol 22 (5) ◽  
pp. 2681
Author(s):  
Michelle A. Erickson ◽  
Elizabeth M. Rhea ◽  
Rachel C. Knopp ◽  
William A. Banks
Keyword(s):  
Risk Factors ◽  
Blood Brain Barrier ◽  
Viral Entry ◽  
Neurological Complications ◽  
Neurological Dysfunction ◽  
Brain Barrier ◽  
Cns Infection ◽  
Cytokine Storm ◽  
Blood Brain ◽  
The Brain

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood–brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

scholarly journals The deep and slow breathing characterizing rest favors brain respiratory-drive

2020 ◽  
Author(s):  
Baptiste Girin ◽  
Maxime Juventin ◽  
Samuel Garcia ◽  
Laura Lefèvre ◽  
Corine Amat ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Field Potential ◽  
Brain Regions ◽  
Airflow Rate ◽  
Respiratory Drive ◽  
Nasal Airflow ◽  
Waking And Sleep ◽  
Potential Activity ◽  
Slow Breathing ◽  
The Brain

A respiration-locked activity in the olfactory brain, mainly originating in the mechano-sensitivity of olfactory sensory neurons to air pressure, propagates from the olfactory bulb to the rest of the brain. Interestingly, changes in nasal airflow rate result in reorganization of olfactory bulb response. Therefore, if the respiratory drive of the brain originates in nasal airflow movements, then it should vary with respiration dynamics that occur spontaneously during natural conditions. We took advantage of the spontaneous variations of respiration dynamics during the different waking and sleep states to explore respiratory drive in various brain regions. We analyzed their local field potential activity relative to respiratory signal. We showed that respiration regime was state-specific, and that quiet waking was the only vigilance state during which all the recorded structures can be respiration-driven whatever the respiration frequency. We used a CO2-enriched air to change the respiratory regime associated to each state and, using a respiratory cycle-by-cycle analysis, we evidenced that the large and strong brain entrainment during quiet waking was the consequence of its associated respiration regime consisting in an optimal trade-off between deepness and duration of inspiration. These results show for the first time that changes in respiration regime alter the cortical dynamics and that the respiratory regime associated with rest is optimal for respiration to drive the brain.

scholarly journals Qualitative and Quantitative Analysis of Regional Cerebral Free Fatty Acids in Rats Using the Stable Isotope Labeling Liquid Chromatography–Mass Spectrometry Method

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5163
Author(s):  
Ting Hu ◽  
Quanfei Zhu ◽  
Yuning Hu ◽  
Ghulam Mustafa Kamal ◽  
Yuqi Feng ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Fatty Acids ◽  
Liquid Chromatography ◽  
Olfactory Bulb ◽  
Free Fatty Acids ◽  
Brain Regions ◽  
Liquid Chromatography Mass Spectrometry ◽  
Whole Brain ◽  
The Relationship ◽  
The Brain

Free fatty acids serve as important bioactive molecules in the brain. They are involved in message transfer in the brain. There are many reports available in the literature regarding the role of cerebral fatty acids in message transfer; however, most of the studies are mainly focused on limited fatty acid species or only a few specific brain regions. To understand the relationship between cerebral functions and free fatty acids, it is necessary to investigate the distribution of the free fatty acids among different regions in the whole brain. In this study, free fatty acids were extracted from different brain regions and analyzed qualitatively and quantitatively using the stable isotopic labeling liquid chromatography–mass spectrometry approach. In total, 1008 potential free fatty acids were detected in the whole brain out of which 38 were found to be commonly present in all brain regions. Among different brain regions, the highest and the smallest amounts of potential free fatty acids were detected in the olfactory bulb and cerebellum, respectively. From a statistical point of view, 4-methyl-2-oxovaleric acid, cis-11, 14-eicosadienoic acid, tridecanoic acid, myristic acid, nonadecanoic acid, and arachidic acid were found to significantly vary among the four different brain regions (olfactory bulb, occipital lobe, hippocampus, and cerebellum). The variation in the composition of free fatty acids among different brain regions may be very important for investigating the relationship between free fatty acids and functions of cerebral regions.

scholarly journals The deep and slow breathing characterizing rest favors brain respiratory-drive

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Baptiste Girin ◽  
Maxime Juventin ◽  
Samuel Garcia ◽  
Laura Lefèvre ◽  
Corine Amat ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Field Potential ◽  
Brain Regions ◽  
Respiratory Pattern ◽  
Airflow Rate ◽  
Respiratory Drive ◽  
Nasal Airflow ◽  
Waking And Sleep ◽  
Slow Breathing ◽  
The Brain

AbstractA respiration-locked activity in the olfactory brain, mainly originating in the mechano-sensitivity of olfactory sensory neurons to air pressure, propagates from the olfactory bulb to the rest of the brain. Interestingly, changes in nasal airflow rate result in reorganization of olfactory bulb response. By leveraging spontaneous variations of respiratory dynamics during natural conditions, we investigated whether respiratory drive also varies with nasal airflow movements. We analyzed local field potential activity relative to respiratory signal in various brain regions during waking and sleep states. We found that respiration regime was state-specific, and that quiet waking was the only vigilance state during which all the recorded structures can be respiration-driven whatever the respiratory frequency. Using CO2-enriched air to alter respiratory regime associated to each state and a respiratory cycle based analysis, we evidenced that the large and strong brain drive observed during quiet waking was related to an optimal trade-off between depth and duration of inspiration in the respiratory pattern, characterizing this specific state. These results show for the first time that changes in respiration regime affect cortical dynamics and that the respiratory regime associated with rest is optimal for respiration to drive the brain.

scholarly journals Critical Role for Glial Cells in the Propagation and Spread of Lymphocytic Choriomeningitis Virus in the Developing Rat Brain

2002 ◽  
Vol 76 (13) ◽  
pp. 6618-6635 ◽  
Author(s):  
Daniel J. Bonthius ◽  
Jolonda Mahoney ◽  
Michael J. Buchmeier ◽  
Bahri Karacay ◽  
Derek Taggard
Keyword(s):  
Olfactory Bulb ◽  
Dentate Gyrus ◽  
Rat Brain ◽  
Glial Cells ◽  
Brain Regions ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Pathological Changes ◽  
Developing Rat ◽  
The Brain

ABSTRACT Inoculation of the neonatal rat with lymphocytic choriomeningitis virus (LCMV) results in the selective infection of several neuronal populations and in focal pathological changes. However, the pathway by which LCMV reaches the susceptible neurons has not been described, and the nature and time course of the pathological changes induced by the infection are largely unknown. This study examined the sequential migration of LCMV in the developing rat brain and compared the pathological changes among infected brain regions. The results demonstrate that astrocytes and Bergmann glia cells are the first cells of the brain parenchyma infected with LCMV and that the virus spreads across the brain principally via contiguous glial cells. The virus then spreads from glial cells into neurons. However, not all neurons are susceptible to infection. LCMV infects neurons in only four specific brain regions: the cerebellum, olfactory bulb, dentate gyrus, and periventricular region. The virus is then cleared from glial cells but persists in neurons. LCMV induces markedly different pathological changes in each of the four infected regions. The cerebellum undergoes an acute and permanent destruction, while the olfactory bulb is acutely hypoplastic but recovers fully with age. Neurons of the dentate gyrus are unaffected in the acute phase but undergo a delayed-onset mortality. In contrast, the periventricular region has neither acute nor late-onset cell loss. Thus, LCMV infects four specific brain regions in the developing brain by spreading from glial cells to neurons and then induces substantially different pathological changes with diverse time courses in each of the four infected regions.

scholarly journals Regional Expression of npy mRNA Paralogs in the Brain of Atlantic Salmon (Salmo salar, L.) and Response to Fasting

2021 ◽  
Vol 12 ◽  
Author(s):  
Ingvill Tolås ◽  
Tharmini Kalananthan ◽  
Ana S. Gomes ◽  
Floriana Lai ◽  
Sissel Norland ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Olfactory Bulb ◽  
Mrna Expression ◽  
Salmo Salar ◽  
Brain Regions ◽  
The Other ◽  
Human Homolog ◽  
Mature Peptide ◽  
The Brain ◽  
Mrna Expression Levels

Neuropeptide Y (NPY) is known as a potent orexigenic signal in vertebrates, but its role in Atlantic salmon has not yet been fully established. In this study, we identified three npy paralogs, named npya1, npya2, and npyb, in the Atlantic salmon genome. In silico analysis revealed that these genes are well conserved across the vertebrate’s lineage and the mature peptide sequences shared at least 77% of identity with the human homolog. We analyzed mRNA expression of npy paralogs in eight brain regions of Atlantic salmon post-smolt, and the effect of 4 days of fasting on the npy expression level. Results show that npya1 was the most abundant paralog, and was predominantly expressed in the telencephalon, followed by the midbrain and olfactory bulb. npya2 mRNA was highly abundant in hypothalamus and midbrain, while npyb was found to be highest expressed in the telencephalon, with low mRNA expression levels detected in all the other brain regions. 4 days of fasting resulted in a significant (p < 0.05) decrease of npya1 mRNA expression in the olfactory bulb, increased npya2 mRNA expression in the midbrain and decreased npyb mRNA expression in the pituitary. In the hypothalamus, the vertebrate appetite center, expression of the npy paralogs was not significantly affected by feeding status. However, we observed a trend of increased npya2 mRNA expression (p = 0.099) following 4 days of fasting. Altogether, our findings provide a solid basis for further research on appetite and energy metabolism in Atlantic salmon.

scholarly journals Paraquat Inhalation, a Translationally Relevant Route of Exposure: Disposition to the Brain and Male-Specific Olfactory Impairment in Mice

2020 ◽  
Author(s):  
Timothy Anderson ◽  
Alyssa K Merrill ◽  
Matthew L Eckard ◽  
Elena Marvin ◽  
Katherine Conrad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Olfactory Bulb ◽  
Brain Regions ◽  
Olfactory Discrimination ◽  
Olfactory Impairment ◽  
Route Of Exposure ◽  
Male Specific ◽  
The Brain ◽  
Lung And Kidney

Abstract Epidemiological and experimental studies have associated oral and systemic exposures to the herbicide paraquat (PQ) with Parkinson’s disease. Despite recognition that airborne particles and solutes can be directly translocated to the brain via olfactory neurons, the potential for inhaled PQ to cause olfactory impairment has not been investigated. This study sought to determine if prolonged low-dose inhalation exposure to PQ would lead to disposition to the brain and olfactory impairment, a prodromal feature of Parkinson’s disease. Adult male and female C57BL/6J mice were exposed to PQ aerosols in a whole-body inhalation chamber for 4 h/day, 5 days/week for 4 weeks. Subsets of mice were sacrificed during and after exposure and PQ concentrations in various brain regions (olfactory bulb, striatum, midbrain, and cerebellum) lung, and kidney were quantified via mass spectrometry. Alterations in olfaction were examined using an olfactory discrimination paradigm. PQ inhalation resulted in an appreciable burden in all examined brain regions, with the highest burden observed in the olfactory bulb, consistent with nasal olfactory uptake. PQ was also detected in the lung and kidney, yet PQ levels in all tissues returned to control values within 4 weeks post exposure. PQ inhalation caused persistent male-specific deficits in olfactory discrimination. No effects were observed in females. These data support the importance of route of exposure in determination of safety estimates for neurotoxic pesticides, such as PQ. Accurate estimation of the relationship between exposure and internal dose is critical for risk assessment and public health protection.

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