Raam T, McAvoy KM, Besnard A, Veenema A, Sahay A.
PMID: 29222469 | DOI: 10.1038/s41467-017-02173-0
Oxytocin receptor (Oxtr) signaling in neural circuits mediating discrimination of social stimuli and affiliation or avoidance behavior is thought to guide social recognition. Remarkably, the physiological functions of Oxtrs in the hippocampus are not known. Here we demonstrate using genetic and pharmacological approaches that Oxtrs in the anterior dentate gyrus (aDG) and anterior CA2/CA3 (aCA2/CA3) of mice are necessary for discrimination of social, but not non-social, stimuli. Further, Oxtrs in aCA2/CA3 neurons recruit a population-based coding mechanism to mediate social stimuli discrimination. Optogenetic terminal-specific attenuation revealed a critical role for aCA2/CA3 outputs to posterior CA1 for discrimination of social stimuli. In contrast, aCA2/CA3 projections to aCA1 mediate discrimination of non-social stimuli. These studies identify a role for an aDG-CA2/CA3 axis of Oxtr expressing cells in discrimination of social stimuli and delineate a pathway relaying social memory computations in the anterior hippocampus to the posterior hippocampus to guide social recognition.
"Boldog E, Bakken TE, Hodge RD, Novotny M, Aevermann BD, Baka J, Bordé S, Close JL, Diez-Fuertes F, Ding SL, Faragó N, Kocsis AK, Kovács B, Maltzer Z, McCorrison JM, Miller JA, Molnár G, Oláh G, Ozsvár A, Rózsa M, Shehata SI, Smith KA, Sunkin SM, Tran D
PMID: 30150662 | DOI: 10.1038/s41593-018-0205-2
We describe convergent evidence from transcriptomics, morphology, and physiology for a specialized GABAergic neuron subtype in human cortex. Using unbiased single-nucleus RNA sequencing, we identify ten GABAergic interneuron subtypes with combinatorial gene signatures in human cortical layer 1 and characterize a group of human interneurons with anatomical features never described in rodents, having large 'rosehip'-like axonal boutons and compact arborization. These rosehip cells show an immunohistochemical profile (GAD1+CCK+, CNR1-SST-CALB2-PVALB-) matching a single transcriptomically defined cell type whose specific molecular marker signature is not seen in mouse cortex. Rosehip cells in layer 1 make homotypic gap junctions, predominantly target apical dendritic shafts of layer 3 pyramidal neurons, and inhibit backpropagating pyramidal action potentials in microdomains of the dendritic tuft. These cells are therefore positioned for potent local control of distal dendritic computation in cortical pyramidal neurons.
Nat Neurosci. 2019 Jan;22(1):47-56.
Fu H, Possenti A, Freer R, Nakano Y, Villegas NCH, Tang M, Cauhy PVM, Lassus BA, Chen S, Fowler SL, Figueroa HY, Huey ED, Johnson GVW, Vendruscolo M, Duff KE.
PMID: 30559469 | DOI: 10.1038/s41593-018-0298-7
Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.
Folorunso, OO;Brown, SE;Baruah, J;Harvey, TL;Jami, SA;Radzishevsky, I;Wolosker, H;McNally, JM;Gray, JA;Vasudevan, A;Balu, DT;
PMID: 37311798 | DOI: 10.1038/s41598-023-35615-5
The proper development and function of telencephalic GABAergic interneurons is critical for maintaining the excitation and inhibition (E/I) balance in cortical circuits. Glutamate contributes to cortical interneuron (CIN) development via N-methyl-D-aspartate receptors (NMDARs). NMDAR activation requires the binding of a co-agonist, either glycine or D-serine. D-serine (co-agonist at many mature forebrain synapses) is racemized by the neuronal enzyme serine racemase (SR) from L-serine. We utilized constitutive SR knockout (SR-/-) mice to investigate the effect of D-serine availability on the development of CINs and inhibitory synapses in the prelimbic cortex (PrL). We found that most immature Lhx6 + CINs expressed SR and the obligatory NMDAR subunit NR1. At embryonic day 15, SR-/- mice had an accumulation of GABA and increased mitotic proliferation in the ganglionic eminence and fewer Gad1 + (glutamic acid decarboxylase 67 kDa; GAD67) cells in the E18 neocortex. Lhx6 + cells develop into parvalbumin (PV+) and somatostatin (Sst+) CINs. In the PrL of postnatal day (PND) 16 SR-/- mice, there was a significant decrease in GAD67+ and PV+, but not SST + CIN density, which was associated with reduced inhibitory postsynaptic potentials in layer 2/3 pyramidal neurons. These results demonstrate that D-serine availability is essential for prenatal CIN development and postnatal cortical circuit maturation.
American Journal of Transplantation
Saharia, KK;Ramelli, SC;Stein, SR;Roder, AE;
| DOI: 10.1016/j.ajt.2022.09.001
Although the risk of SARS-CoV-2 transmission through lung transplantation from acutely infected donors is high, the risks of virus transmission and long-term lung allograft outcomes are not as well described when using pulmonary organs from COVID-19-recovered donors. We describe successful lung transplantation for a COVID-19-related lung injury using lungs from a COVID-19-recovered donor who was retrospectively found to have detectable genomic SARS-CoV-2 RNA in the lung tissue by multiple highly sensitive assays. However, SARS-CoV-2 subgenomic RNA (sgRNA), a marker of viral replication, was not detectable in the donor respiratory tissues. One year after lung transplantation, the recipient has a good functional status, walking 1 mile several times per week without the need for supplemental oxygen and without any evidence of donor-derived SARS-CoV-2 transmission. Our findings highlight the limitations of current clinical laboratory diagnostic assays in detecting the persistence of SARS-CoV-2 RNA in the lung tissue. The persistence of SARS-CoV-2 RNA in the donor tissue did not appear to represent active viral replication via sgRNA testing and, most importantly, did not negatively impact the allograft outcome in the first year after lung transplantation. sgRNA is easily performed and may be a useful assay for assessing viral infectivity in organs from donors with a recent infection.
Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of COVID-19 death
Szekely, L;Bozoky, B;Bendek, M;Ostad, M;Lavignasse, P;Haag, L;Wu, J;Jing, X;Gupta, S;Saccon, E;Sönnerborg, A;Cao, Y;Björnstedt, M;Szakos, A;
PMID: 34056141 | DOI: 10.1016/j.heliyon.2021.e07134
Most COVID-19 victims are old and die from unrelated causes. Here we present twelve complete autopsies, including two rapid autopsies of young patients where the cause of death was COVID-19 ARDS. The main virus induced pathology was in the lung parenchyma and not in the airways. Most coagulation events occurred in the intra-alveolar and not in the intra-vascular space and the few thrombi were mainly composed of aggregated thrombocytes. The dominant inflammatory response was the massive accumulation of CD163 + macrophages and the disappearance of T killer, NK and B-cells. The virus was replicating in the pneumocytes and macrophages but not in bronchial epithelium, endothelium, pericytes or stromal cells. The lung consolidations were produced by a massive regenerative response, stromal and epithelial proliferation and neovascularization. We suggest that thrombocyte aggregation inhibition, angiogenesis inhibition and general proliferation inhibition may have a roll in the treatment of advanced COVID-19 ARDS.
Brain Struct Funct. 2014 Nov 27.
de Kloet AD, Wang L, Ludin JA, Smith JA, Pioquinto DJ, Hiller H, Steckelings UM, Scheuer DA, Sumners C, Krause EG.
PMID: 25427952
Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual immunohistochemistry (IHC)/ISH studies conducted in AT2R-eGFP reporter mice found that eGFP and AT2R mRNA were highly co-localized within the brain. Qualitative analysis of eGFP immunoreactivity in the brain then revealed localization to neurons within nuclei that regulate blood pressure, metabolism, and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]), as well as limbic and cortical areas known to impact stress responding and mood. Subsequently, dual IHC/ISH studies uncovered the phenotype of specific populations of AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-1 (80.3 ± 2.8 %), while a smaller subset express vesicular glutamate transporter-2 (18.2 ± 2.9 %) or AT1R (8.7 ± 1.0 %). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular nucleus (PVN) of the hypothalamus, eGFP immunoreactivity is localized to efferents terminating in the PVN and within GABAergic neurons surrounding this nucleus. These studies demonstrate that central AT2R are positioned to regulate blood pressure, metabolism, and stress responses.
Roczkowsky, A;Limonta, D;Fernandes, JP;Branton, WG;Clarke, M;Hlavay, B;Noyce, RS;Joseph, JT;Ogando, NS;Das, SK;Elaish, M;Arbour, N;Evans, DH;Langdon, K;Hobman, TC;Power, C;
PMID: 37190821 | DOI: 10.1002/ana.26679
Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during SARS-CoV-2 infection using a multiplatform strategy.Brain tissues from COVID-19 (n=12) and other disease control (ODC) (n=12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by ddPCR, RT-qPCR and immunodetection methods.SARS-CoV-2 RNA was detected in the CNS of four patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p<0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11β and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 patients compared to ODCs (p<0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p<0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p<0.05).COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. This article is protected by
González-Mesa, E;García-Fuentes, E;Carvia-Pontiasec, R;Lavado-Fernández, A;Cuenca-Marín, C;Suárez-Arana, M;Blasco-Alonso, M;Benítez-Lara, B;Mozas-Benítez, L;González-Cazorla, A;Egeberg-Neverdal, H;Jiménez-López, J;
| DOI: 10.3390/diagnostics12020245
(1) Background: Little is known about the effects of SARS-CoV-2 on the placenta, and whether the maternal inflammatory response is transmitted vertically. This research aims to provide information about the effects of SARS-CoV-2 infection on maternal and fetal immunity. (2) Methods: We have studied placental changes and humoral and cellular immunity in maternal and umbilical cord blood (UCB) samples from a group of pregnant women delivering after the diagnosis of SARS-CoV-2 infection during pregnancy. IgG and IgM SARS-CoV-2 antibodies, Interleukin 1b (IL1b), Interleukin 6 (IL6), and gamma-Interferon (IFN-γ), have been studied in the UCB samples. Lymphocyte subsets were studied according to CD3, CD8, CD4, CD34, and invariant natural Killer T cells (iNKT) markers. We used in situ hybridization techniques for the detection of viral RNA in placentas. (3) Results: During the study period, 79 pregnant women and their corresponding newborns were recruited. The main gestational age at the time of delivery was 39.1 weeks (SD 1.3). We did not find traces of the SARS-CoV-2 virus RNA in any of the analyzed placental samples. Detectable concentrations of IgG anti-SARS-CoV-2 antibodies, IL1b, IL6, and IFN-γ, in UCB were found in all cases, but IgM antibodies anti-ARS-CoV-2 were systematically undetectable. We found significant correlations between fetal CD3+ mononuclear cells and UCB IgG concentrations. We also found significant correlations between UCB IgG concentrations and fetal CD3+/CD4+, as well as CD3+/CD8+ T cells subsets. We also discovered that fetal CD3+/CD8+ cell counts were significantly higher in those cases with placental infarctions. (4) Conclusion: we have not verified the placental transfer of SARS-CoV-2. However, we have discovered that a significant immune response is being transmitted to the fetus in cases of SARS-CoV-2 maternal infection.
Diamond, M;Halfmann, P;Maemura, T;Iwatsuki-Horimoto, K;Iida, S;Kiso, M;Scheaffer, S;Darling, T;Joshi, A;Loeber, S;Foster, S;Ying, B;Whitener, B;Floyd, K;Ujie, M;Nakajima, N;Ito, M;Wright, R;Uraki, R;Li, R;Sakai, Y;Liu, Y;Larson, D;Osorio, J;Hernandez-Ortiz, J;ÄŒiuoderis, K;Florek, K;Patel, M;Bateman, A;Odle, A;Wong, LY;Wang, Z;Edara, VV;Chong, Z;Thackray, L;Ueki, H;Yamayoshi, S;Imai, M;Perlman, S;Webby, R;Seder, R;Suthar, M;Garcia-Sastre, A;Schotsaert, M;Suzuki, T;Boon, A;Kawaoka, Y;Douek, D;Moliva, J;Sullivan, N;Gagne, M;Ransier, A;Case, J;Jeevan, T;Franks, J;Fabrizio, T;DeBeauchamp, J;Kercher, L;Seiler, P;Singh, G;Warang, P;Gonzalez-Reiche, AS;Sordillo, E;van Bakel, H;Simon, V;
PMID: 34981044 | DOI: 10.21203/rs.3.rs-1211792/v1
Despite the development and deployment of antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. The recent emergence of B.1.1.529, the Omicron variant1,2, which has more than 30 mutations in the spike protein, has raised concerns for escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in pre-clinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of multiple B.1.1.529 Omicron isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2) expressing mice and hamsters. Despite modeling and binding data suggesting that B.1.1.529 spike can bind more avidly to murine ACE2, we observed attenuation of infection in 129, C57BL/6, and BALB/c mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. Although K18-hACE2 transgenic mice sustained infection in the lungs, these animals did not lose weight. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from multiple independent laboratories of the SAVE/NIAID network with several different B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.
Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Bearse, M;Hung, YP;Krauson, AJ;Bonanno, L;Boyraz, B;Harris, CK;Helland, TL;Hilburn, CF;Hutchison, B;Jobbagy, S;Marshall, MS;Shepherd, DJ;Villalba, JA;Delfino, I;Mendez-Pena, J;Chebib, I;Newton-Cheh, C;Stone, JR;
PMID: 33727695 | DOI: 10.1038/s41379-021-00790-1
COVID-19 has been associated with cardiac injury and dysfunction. While both myocardial inflammatory cell infiltration and myocarditis with myocyte injury have been reported in patients with fatal COVID-19, clinical-pathologic correlations remain limited. The objective was to determine the relationships between cardiac pathological changes in patients dying from COVID-19 and cardiac infection by SARS-CoV-2, laboratory measurements, clinical features, and treatments. In a retrospective study, 41 consecutive autopsies of patients with fatal COVID-19 were analyzed for the associations between cardiac inflammation, myocarditis, cardiac infection by SARS-CoV-2, clinical features, laboratory measurements, and treatments. Cardiac infection was assessed by in situ hybridization and NanoString transcriptomic profiling. Cardiac infection by SARS-CoV-2 was present in 30/41 cases: virus+ with myocarditis (n = 4), virus+ without myocarditis (n = 26), and virus- without myocarditis (n = 11). In the cases with cardiac infection, SARS-CoV-2+ cells in the myocardium were rare, with a median density of 1 cell/cm2. Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01). Myocarditis was more prevalent with IL-6 blockade than with nonbiologic immunosuppression, primarily glucocorticoids (2/3 vs 0/14; P = 0.02). Overall, SARS-CoV-2 cardiac infection was less prevalent in patients treated with nonbiologic immunosuppression (7/14 vs 21/24; P = 0.02). Myocardial macrophage and lymphocyte densities overall were positively correlated with the duration of symptoms but not with underlying comorbidities. In summary, cardiac infection with SARS-CoV-2 is common among patients dying from COVID-19 but often with only rare infected cells. Cardiac infection by SARS-CoV-2 is associated with more cardiac inflammation and electrocardiographic changes. Nonbiologic immunosuppression is associated with lower incidences of myocarditis and cardiac infection by SARS-CoV-2.
The American journal of pathology
Lee, YJ;Seok, SH;Lee, NY;Choi, HJ;Lee, YW;Chang, HJ;Hwang, JY;On, DI;Noh, HA;Lee, SB;Kwon, HK;Yun, JW;Shin, JS;Seo, JY;Nam, KT;Lee, H;Lee, HY;Park, JW;Seong, JK;
PMID: 37024046 | DOI: 10.1016/j.ajpath.2023.03.008
The disease severity of coronavirus disease 2019 (COVID-19) varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in patients with COVID-19, but the mechanisms involved remain elusive. In this study, human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2 expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.
