Cholecystokinin neurons in mouse suprachiasmatic nucleus regulate the robustness of circadian clock

Neuron

2023 May 07

Xie, L;Xiong, Y;Ma, D;Shi, K;Chen, J;Yang, Q;Yan, J;
PMID: 37172583 | DOI: 10.1016/j.neuron.2023.04.016

The suprachiasmatic nucleus (SCN) can generate robust circadian behaviors in mammals under different environments, but the underlying neural mechanisms remained unclear. Here, we showed that the activities of cholecystokinin (CCK) neurons in the mouse SCN preceded the onset of behavioral activities under different photoperiods. CCK-neuron-deficient mice displayed shortened free-running periods, failed to compress their activities under a long photoperiod, and developed rapid splitting or became arrhythmic under constant light. Furthermore, unlike vasoactive intestinal polypeptide (VIP) neurons, CCK neurons are not directly light sensitive, but their activation can elicit phase advance and counter light-induced phase delay mediated by VIP neurons. Under long photoperiods, the impact of CCK neurons on SCN dominates over that of VIP neurons. Finally, we found that the slow-responding CCK neurons control the rate of recovery during jet lag. Together, our results demonstrated that SCN CCK neurons are crucial for the robustness and plasticity of the mammalian circadian clock.

Dynamic cellular changes in acute kidney injury caused by different ischemia time

iScience

2023 May 01

Shan, D;Wang, Y;Chang, Y;Cui, H;Tao, M;Sheng, Y;Kang, H;Jia, P;Song, J;
| DOI: 10.1016/j.isci.2023.106646

Ischemia reperfusion injury (IRI), often related to surgical procedures, is one of the important causes of acute kidney injury (AKI). To decipher the dynamic process of AKI caused by IRI (with prolonged ischemia phase), we performed single-cell RNA sequencing (scRNA-seq) of clinically relevant IRI murine model with different ischemic intervals. We discovered that Slc5a2hi proximal tubular cells were susceptible to AKI and highly expressed neutral amino acid transporter gene Slc6a19, which was dramatically decreased over the time course. With the usage of mass spectrometry-based metabolomic analysis, we detected that the level of neutral amino acid isoleucine dropped off in AKI mouse plasma metabolites. And the reduction of plasma isoleucine was also verified in patients with cardiac surgery-associated acute kidney injury (CSA-AKI). The findings advanced the understanding of dynamic process of AKI and introduced reduction of isoleucine as a potential biomarker for CSA-AKI.

Immune priming prior to pathogen exposure sheds light on the relationship between host, microbiome and pathogen in disease

Royal Society open science

2023 Feb 01

Kaganer, AW;Ossiboff, RJ;Keith, NI;Schuler, KL;Comizzoli, P;Hare, MP;Fleischer, RC;Gratwicke, B;Bunting, EM;
PMID: 36756057 | DOI: 10.1098/rsos.220810

Dynamic interactions between host, pathogen and host-associated microbiome dictate infection outcomes. Pathogens including Batrachochytrium dendrobatidis (Bd) threaten global biodiversity, but conservation efforts are hindered by limited understanding of amphibian host, Bd and microbiome interactions. We conducted a vaccination and infection experiment using Eastern hellbender salamanders (Cryptobranchus alleganiensis alleganiensis) challenged with Bd to observe infection, skin microbial communities and gene expression of host skin, pathogen and microbiome throughout the experiment. Most animals survived high Bd loads regardless of their vaccination status and vaccination did not affect pathogen load, but host gene expression differed based on vaccination. Oral vaccination (exposure to killed Bd) stimulated immune gene upregulation while topically and sham-vaccinated animals did not significantly upregulate immune genes. In early infection, topically vaccinated animals upregulated immune genes but orally and sham-vaccinated animals downregulated immune genes. Bd increased pathogenicity-associated gene expression in late infection when Bd loads were highest. The microbiome was altered by Bd, but there was no correlation between anti-Bd microbe abundance or richness and pathogen burden. Our observations suggest that hellbenders initially generate a vigorous immune response to Bd, which is ineffective at controlling disease and is subsequently modulated. Interactions with antifungal skin microbiota did not influence disease progression.

Neuronal signal-regulatory protein alpha drives microglial phagocytosis by limiting microglial interaction with CD47 in the retina

Immunity

2022 Nov 09

Jiang, D;Burger, CA;Akhanov, V;Liang, JH;Mackin, RD;Albrecht, NE;Andrade, P;Schafer, DP;Samuel, MA;
PMID: 36379210 | DOI: 10.1016/j.immuni.2022.10.018

Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals that control this phagocytic clockwork remain largely undefined. Here, we show that neuronal signal-regulatory protein alpha (SIRPα) is a permissive cue for microglial phagocytosis in the developing murine retina. Removal of neuronal, but not microglial, SIRPα reduced microglial phagocytosis, increased synpase numbers, and impaired circuit function. Conversely, prolonging neuronal SIRPα expression extended developmental microglial phagocytosis. These outcomes depended on the interaction of presynaptic SIRPα with postsynaptic CD47. Global CD47 deficiency modestly increased microglial phagocytosis, while CD47 overexpression reduced it. This effect was rescued by coexpression of neuronal SIRPα or codeletion of neuronal SIRPα and CD47. These data indicate that neuronal SIRPα regulates microglial phagocytosis by limiting microglial SIRPα access to neuronal CD47. This discovery may aid our understanding of synapse loss in neurological diseases.

Prostaglandin E2 synchronizes lunar-regulated beach spawning in grass puffers

Current biology : CB

2022 Oct 21

Chen, J;Katada, Y;Okimura, K;Yamaguchi, T;Guh, YJ;Nakayama, T;Maruyama, M;Furukawa, Y;Nakane, Y;Yamamoto, N;Sato, Y;Ando, H;Sugimura, A;Tabata, K;Sato, A;Yoshimura, T;
PMID: 36306789 | DOI: 10.1016/j.cub.2022.09.062

Many organisms living along the coastlines synchronize their reproduction with the lunar cycle. At the time of spring tide, thousands of grass puffers (Takifugu alboplumbeus) aggregate and vigorously tremble their bodies at the water's edge to spawn. To understand the mechanisms underlying this spectacular semilunar beach spawning, we collected the hypothalamus and pituitary from male grass puffers every week for 2 months. RNA sequencing (RNA-seq) analysis identified 125 semilunar genes, including genes crucial for reproduction (e.g., gonadotropin-releasing hormone 1 [gnrh1], luteinizing hormone β subunit [lhb]) and receptors for pheromone prostaglandin E (PGE). PGE2 is secreted into the seawater during the spawning, and its administration activates olfactory sensory neurons and triggers trembling behavior of surrounding individuals. These results suggest that PGE2 synchronizes lunar-regulated beach-spawning behavior in grass puffers. To further explore the mechanism that regulates the lunar-synchronized transcription of semilunar genes, we searched for semilunar transcription factors. Spatial transcriptomics and multiplex fluorescent in situ hybridization showed co-localization of the semilunar transcription factor CCAAT/enhancer-binding protein δ (cebpd) and gnrh1, and cebpd induced the promoter activity of gnrh1. Taken together, our study demonstrates semilunar genes that mediate lunar-synchronized beach-spawning behavior. VIDEO ABSTRACT.

Naked Mole-Rat Hyaluronan Synthase 2 Promotes Longevity and Enhances Healthspan in Mice

SSRN Electronic Journal

2022 Aug 11

Zhang, Z;Tian, X;Lu, J;Boit, K;Ablaeva, J;Tolibzoda Zakusilo, F;Emmrich, S;Firsanov, D;Rydkina, E;Biashad, S;Lu, Q;Tyshkovsky, A;Gladyshev, V;Horvath, S;Seluanov, A;Gorbunova, V;
| DOI: 10.2139/ssrn.4185135

Production of abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat. To study whether the benefits of HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.

Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease

Neuron

2022 Jul 21

Otero-Garcia, M;Mahajani, SU;Wakhloo, D;Tang, W;Xue, YQ;Morabito, S;Pan, J;Oberhauser, J;Madira, AE;Shakouri, T;Deng, Y;Allison, T;He, Z;Lowry, WE;Kawaguchi, R;Swarup, V;Cobos, I;
PMID: 35882228 | DOI: 10.1016/j.neuron.2022.06.021

Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.

NIH SenNet Consortium: Mapping Senescent Cells in the Human Body to Understand Health and Disease

Preprint

2022 Jul 12

Lee, P;Blood, P;Börner, K;Campisi, J;Chen, F;Daldrup-Link, H;De Jager, P;Ding, L;Duncan, F;Eickelberg, O;Fan, R;Finkel, T;Garovic, V;Gehlenborg, N;Glass, C;Bar-Joseph, Z;Katiyar, P;Kim, S;Königshoff, M;Kuchel, G;Lee, H;Lee, J;Ma, J;Ma, Q;Melov, S;Metis, K;Mora, A;Musi, N;Neretti, N;Passos, J;Rahman, I;Rivera-Mulia, J;Robson, P;Rojas, M;Roy, A;Schilling, B;Shi, P;Silverstein, J;Suryadevera, V;Xie, J;Wang, J;Wong, A;Niedernhofer, L;
| DOI: 10.20944/preprints202207.0160.v1

Cells respond to a myriad of stressors by senescing, acquiring stable growth arrest, morphologic and metabolic changes, and a senescence-associated-secretory-phenotype (SASP). The heterogeneity of senescent cells (SnCs) and their SASP is vast, yet poorly characterized. SnCs have diverse roles in health and disease and are therapeutically targetable, making characterization of SnCs and harmonization of their nomenclature a priority. The Cellular Senescence Network (SenNet), a NIH Common Fund initiative, will leverage emerging single cell and spatial-omics to identify and map SnCs in numerous organs across the lifespan of humans and mice. A common coordinate framework will integrate the data, using validated, standardized methods, creating public 4-dimensional SnC atlases. Key SenNet deliverables include development of innovative tools/technologies to detect SnCs, biomarker discovery, common annotations to describe SnCs and extensive public data sets. The goal is to comprehensively understand and map SnCs for diagnostic and therapeutic purposes to improve human health.

Recombinant Human Collagen Hydrogel Rapidly Reduces Methylglyoxal Adducts within Cardiomyocytes and Improves Borderzone Contractility after Myocardial Infarction in Mice

Advanced Functional Materials

2022 May 24

McLaughlin, S;Sedlakova, V;Zhang, Q;McNeill, B;Smyth, D;Seymour, R;Davis, D;Ruel, M;Brand, M;Alarcon, E;Suuronen, E;
| DOI: 10.1002/adfm.202204076

Methylglyoxal (MG) production after myocardial infarction (MI) leads to advanced glycation end-product formation, adverse remodeling, and loss of cardiac function. The extracellular matrix (ECM) is a main target for MG glycation. This suggests that ECM-mimicking biomaterial therapies may protect the post-MI environment by removing MG. In this study, mechanisms by which a recombinant human collagen type I hydrogel therapy confers cardioprotection are investigated. One-week post-MI, mice receive intramyocardial injection of hydrogel or PBS. The hydrogel improves border zone contractility after 2 days, which is maintained for 28 days. RNA sequencing shows that hydrogel treatment decreases the expression of erythroid differentiation regulator 1, a factor associated with apoptosis. Hydrogel treatment reduces cardiomyocyte apoptosis and oxidative stress at 2 days with greater myocardial salvage seen at 28 days. The hydrogel located at the epicardial surface is modified by MG, and less MG-modified proteins are observed in the underlying myocardium of hydrogel-treated mice. Biomaterials that can be a target for MG glycation may act as a sponge to remove MG from the myocardium post-MI. This leads to less oxidative stress, greater survival and contractility of cardiomyocytes, which altogether suggests a novel mechanism by which biomaterials improve function of the infarcted heart.

Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine

Neuron

2022 Mar 25

Yang, L;Xu, M;Bhuiyan, SA;Li, J;Zhao, J;Cohrs, RJ;Susterich, JT;Signorelli, S;Green, U;Stone, JR;Levy, D;Lennerz, JK;Renthal, W;
PMID: 35349784 | DOI: 10.1016/j.neuron.2022.03.003

Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes that are involved remain unclear. We thus developed a cell atlas in which human and mouse trigeminal ganglia are transcriptionally and epigenomically profiled at single-cell resolution. These data describe evolutionarily conserved and human-specific gene expression patterns within each trigeminal ganglion cell type, as well as the transcription factors and gene regulatory elements that contribute to cell-type-specific gene expression. We then leveraged these data to identify trigeminal ganglion cell types that are implicated both by human genetic variation associated with migraine and two mouse models of headache. This trigeminal ganglion cell atlas improves our understanding of the cell types, genes, and epigenomic features involved in headache pathophysiology and establishes a rich resource of cell-type-specific molecular features to guide the development of more selective treatments for headache and facial pain.

Excitatory SST Neurons in the Medial Paralemniscal Nucleus Control Repetitive Self-Grooming and Encode Reward

SSRN Electronic Journal

2022 Jan 22

Sun, J;Yuan, Y;Wu, X;Liu, A;Wang, J;Yang, S;Liu, B;Kong, Y;Wang, L;Li, Q;Zhang, S;Yuan, T;Xu, T;Huang, J;
| DOI: 10.2139/ssrn.4013919

The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means for emotion regulation upon stress exposure. However, it is unclear about the neurological mechanism on how repetitive behaviors affect emotion regulation to cope with stress. Here, we identify that excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPLSST neurons) control self-grooming and encode reward. MPLSST neuronal activity is responsible for self-grooming initiation and maintenance. Loss-of-function of MPLSST neurons attenuates both self-grooming motor actions and anxiety alleviation upon stress exposure. Activating MPLSST neurons generate reward and drive reinforcement through eliciting dopamine release in the downstream target of the ventral tegmental area (VTA), and neuropeptide SST facilitates the rewarding impact of MPLSST neurons. MPLSST neuron-mediated self-grooming is triggered by inputs from the central amygdala (CeA). Our study validates a CeA-MPLSST-VTADA circuit mediating the impact of self-grooming on emotion regulation to cope with stress through generating reward and pleasurable feelings.

DMD-TREATMENT: EP. 147 2.5-years of vamorolone treatment in Duchenne muscular dystrophy: Results of an open label long-term extension

Neuromuscular Disorder

2021 Jan 01

Hoffman, E;Dang, U;Clemens, P;
| DOI: Genotypes were determined by PCR using commercial vendors (Transnetyx, Cordova, TN, USA).

Vamorolone is a first-in-class steroidal anti-inflammatory drug with novel structure/activity relationships with glucocorticoid and mineralocorticoid receptor targets compared to deflazacort or prednisone. Published open-label dose-finding studies (0.25-6.0 mg/kg/day) in DMD showed significant motor function improvement over 24 weeks for 2.0 and 6.0 mg/kg/day dose groups (n=48; age 4 to 6-month delay and maintained a higher dose through the remaining study period. Analyses of disease trajectories showed a strong effect of age at initiation of treatment. Subjects initiating treatment at 4-5 years showed highest clinical outcome performance levels as well as a delayed decline of motor function compared to subjects initially treated with low doses (0.25 or 0.75 mg/kg/day). Stratification of participants by treatment period at high doses (2.5 years; or delayed start 2.0 years), and/or by age showed data consistent with a disease modifying effect for many outcome measures. Vamorolone treatment was not associated with typical safety concerns of corticosteroid treatment (slowing of linear growth, insulin resistance, decreases in osteocalcin).

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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