Digital Commons Network^™

Rhoa-Rock Signaling As A Therapeutic Target In Traumatic Brain Injury, Shalaka Mulherkar, Kimberley F Tolias

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBIs, which range in severity from mild to severe, occur when a traumatic event, such as a fall, a traffic accident, or a blow, causes the brain to move rapidly within the skull, resulting in damage. Long-term consequences of TBI can include motor and cognitive deficits and emotional disturbances that result in a reduced quality of life and work productivity. Recovery from TBI can be challenging due to a lack of effective treatment options for repairing TBI-induced neural damage and alleviating functional impairments. Central nervous system (CNS) …

An Artificial Habitat Increases The Reproductive Fitness Of A Range-Shifting Species Within A Newly Colonized Ecosystem, Zachary J. Cannizzo, Susan Q. Lang, Bryan Benitez-Nelson, Blaine D. Griffen

Faculty Publications

When a range-shifting species colonizes an ecosystem it has not previously inhabited, it may experience suboptimal conditions that challenge its continued persistence and expansion. Some impacts may be partially mitigated by artificial habitat analogues: artificial habitats that more closely resemble a species' historic ecosystem than the surrounding habitat. If conditions provided by such habitats increase reproductive success, they could be vital to the expansion and persistence of range-shifting species. We investigated the reproduction of the mangrove tree crab Aratus pisonii in its historic mangrove habitat, the suboptimal colonized salt marsh ecosystem, and on docks within the marsh, an artificial mangrove …

Natural Sources And Bioactivities Of 2,4-Di-Tert-Butylphenol And Its Analogs, Fuqiang Zhao, Ping Wang, Rima D. Lucardi, Zushang Su, Shiyou Li

NCPC Publications and Patents

2,4-Di-tert-butylphenol or 2,4-bis(1,1-dimethylethyl)-phenol (2,4-DTBP) is a common toxic secondary metabolite produced by various groups of organisms. The biosources and bioactivities of 2,4-DTBP have been well investigated, but the phenol has not been systematically reviewed. This article provides a comprehensive review of 2,4-DTBP and its analogs with emphasis on natural sources and bioactivities. 2,4-DTBP has been found in at least 169 species of bacteria (16 species, 10 families), fungi (11 species, eight families), diatom (one species, one family), liverwort (one species, one family), pteridiphyta (two species, two families), gymnosperms (four species, one family), dicots (107 species, 58 families), monocots (22 species, …

Integrative Qtl Analysis Of Gene Expression And Chromatin Accessibility Identifies Multi-Tissue Patterns Of Genetic Regulation., Gregory R Keele, Bryan C Quach, Jennifer W Israel, Grace A Chappell, Lauren Lewis, Alexias Safi, Jeremy M Simon, Paul Cotney, Gregory E Crawford, William Valdar, Ivan Rusyn, Terrence S Furey

Faculty Research 2020

Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. Here we characterize expression and chromatin state dynamics across three tissues-liver, lung, and kidney-in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 …

Exogenous Flupirtine As Potential Treatment For Cln3 Disease, Katia Maalouf, Joelle Makoukji, Sara Saab, Nadine J. Makhoul, Angelica V. Carmona, Nihar Kinarivala, Noël Ghanem, Paul C. Trippier, Rose-Mary Boustany

Journal Articles: Pharmaceutical Sciences

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3^Δex7/8 mice. WT/Cln3^Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in …

Editorial: Structure, Isotypes, Targets, And Post-Translational Modifications Of Immunoglobulins And Their Role In Infection, Inflammation And Autoimmunity, Jean Harb, Bridget S. Wilson, Sylvie Hermouet

Pathology Research and Scholarship

EDITORIAL published: 07 August 2020 doi: 10.3389/fimmu.2020.01761 Frontiers in Immunology | www.frontiersin.org 1 August 2020 | Volume 11 | Article 1761 Edited by: Deborah K. Dunn-Walters, University of Surrey, United Kingdom Reviewed by: Roberta Pelanda, University of Colorado School of Medicine, United States *Correspondence: Sylvie Hermouet [email protected] Specialty section: This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology Received: 29 May 2020 Accepted: 30 June 2020 Published: 07 August 2020 Citation: Harb J, Wilson BS and Hermouet S (2020) Editorial: Structure, Isotypes, Targets, and Post-translational Modifications of Immunoglobulins and Their Role in Infection, …

Detedit: A Graphical User Interface For Annotating And Editing Events Detected In Long-Term Acoustic Monitoring Data, Alba Solsona-Berga, Kaitlin E. Frasier, Simone Baumann-Pickering, Sean M. Wiggins, John A. Hildebrand

C-IMAGE Publications

Passive acoustic monitoring has become an important data collection method, yielding massive datasets replete with biological, environmental and anthropogenic information. Automated signal detectors and classifiers are needed to identify events within these datasets, such as the presence of species-specific sounds or anthropogenic noise. These automated methods, however, are rarely a complete substitute for expert analyst review. The ability to visualize and annotate acoustic events efficiently can enhance scientific insights from large, previously intractable datasets. A MATLAB-based graphical user interface, called DetEdit, was developed to accelerate the editing and annotating of automated detections from extensive acoustic datasets. This tool is highly-configurable …

Glioma-Derived Exosomes Drive The Differentiation Of Neural Stem Cells To Astrocytes, Krishna D. Sharma, Danielle Schaal, Rajshekhar A. Kore, Rabab N. Hamzah, Sahitya Chetan Pandanaboina, Abdallah Hayar, Robert J. Griffin, Malathi Srivatsan, Nathan S. Reyna, Jennifer Yanhua Xie

Arkansas Biosciences Institute

Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, …

N‑Linked Glycosylation Prevents Deamidation Of Glycopeptide And Glycoprotein, Joshua Zhu, Ding Liu, Vy P. Tran, Zhigang Wu, Kuan Jiang, He Zhu, Jiabin Zhang, Christopher Gibbons, Bingzhong Xue, Hang Shi, Peng George Wang

Faculty Work Comprehensive List

Deamidation has been recognized as a common spontaneous pathway of protein degradation and a prevalent concern in the pharmaceutical industry; deamidation caused the reduction of protein/peptide drug efficacy and shelf life in several cases. More importantly, deamidation of physiological proteins is related to several human diseases and considered a "timer" for the diseases. N-linked glycosylation has a variety of significant biological functions, and it interestingly occurs right on the deamidation site-asparagine. It has been perceived that N-glycosylation could prevent deamidation, but experimental support is still lacking for clearly understanding the role of N-glycosylation on deamidation. Our results presented that deamidation …

Ampk In The Ventromedial Nucleus Of The Hypothalamus: A Key Regulator For Thermogenesis, Hailan Liu, Yong Xu, Fang Hu

Children’s Nutrition Research Center Staff Publications

Obesity has become a global health issue, but effective therapies remain very limited. Adaptive thermogenesis promotes weight loss by dissipating energy in the form of heat, thereby representing a promising target to counteract obesity. Notably, the regulation of thermogenesis is tightly orchestrated by complex neuronal networks, especially those in the hypothalamus. Recent evidence highlights the importance of adenosine monophosphate-activated protein kinase (AMPK) within the ventromedial nucleus of the hypothalamus (VMH) in modulating thermogenesis. Various molecules, such as GLP-1, leptin, estradiol, and thyroid hormones, have been reported to act on the VMH to inhibit AMPK, which subsequently increases thermogenesis through the …

Functionalized Scaffold And Barrier Membrane With Anti-Bmp-2 Monoclonal Antibodies For Alveolar Ridge Preservation In A Canine Model, Seiko Min, Taewan Kim, Oksu Kim, Carames Goncalo, Tadahiko Utsunomiya, Takashi Matsumoto, Kayo Kuyama, Nikola Angelov

Faculty, Staff and Student Publications

INTRODUCTION: The aim of this study was to investigate the ability of anti-bone morphogenetic protein 2 monoclonal antibody (anti-BMP-2 mAb) to functionalize scaffolds to mediate bone regeneration in a canine model.

MATERIALS AND METHODS: The mandibular right premolar 4 (PM4) was extracted in eight beagle dogs and grafted with anti-BMP-2 mAb+anorganic bovine bone mineral with 10% collagen (ABBM-C) and porcine bilayer native collagen membrane (CM). The ABBM-C and CM were functionalized with either anti-BMP-2 mAb (test group) or an isotype matched control mAb (control group). Animals were euthanized at 12 weeks for radiographic, histologic, and histomorphometric analyses. Outcomes were compared …

Combined Abdominal Heterotopic Heart And Aorta Transplant Model In Mice, Hao Dun, Li Ye, Yuehui Zhu, Brian W Wong

Open Access Publications

BACKGROUND: Allograft vasculopathy (AV) remains a major obstacle to long-term allograft survival. While the mouse aortic transplantation model has been proven as a useful tool for study of the pathogenesis of AV, simultaneous transplantation of the aorta alongside the transplantation of another organ may reveal more clinically relevant mechanisms that contribute to the pathogenesis of chronic allograft rejection. Therefore, we developed a combined abdominal heart and aorta transplantation model in mice which benefits from reducing animal and drug utilization, while providing an improved model to study the progressive nature of AV.

METHODS: The middle of the infrarenal aorta of the …

Chemical Effects Of Dicect Staining Protocols On Fluid-Preserved Avian Specimens, Catherine M. Early, Ashley C. Morhardt, Timothy P. Cleland, Christopher M. Milensky, Gwénaëlle M. Kavich, Helen F. James

Open Access Publications

Diffusible iodine-based contrast-enhanced computed tomography (diceCT) techniques allow visualization of soft tissues of fluid-preserved specimens in three dimensions without dissection or histology. Two popular diceCT stains, iodine-potassium iodide (I2KI) dissolved in water and elemental iodine (I2) dissolved in 100% ethanol (EtOH), yield striking results. Despite the widespread use of these stains in clinical and biological fields, the molecular mechanisms that result in color change and radiopacity attributed to iodine staining are poorly understood. Requests to apply these stains to anatomical specimens preserved in natural history museums are increasing, yet curators have little information about the potential for degradation of treated …

Rev-Erb Agonism Improves Liver Pathology In A Mouse Model Of Nash, Kristine Griffett, Gonzalo Bedia-Diaz, Bahaa Elgendy, Thomas P. Burris

Open Access Publications

Non-alcoholic fatty liver disease (NAFLD) affects a significant number of people worldwide and currently there are no pharmacological treatments. NAFLD often presents with obesity, insulin resistance, and in some cases cardiovascular diseases. There is a clear need for treatment options to alleviate this disease since it often progresses to much more the much more severe non-alcoholic steatohepatitis (NASH). The REV-ERB nuclear receptor is a transcriptional repressor that regulates physiological processes involved in the development of NAFLD including lipogenesis and inflammation. We hypothesized that pharmacologically activating REV-ERB would suppress the progression of fatty liver in a mouse model of NASH. Using …

Client Processing Is Altered By Novel Myopathy-Causing Mutations In The Hsp40 J Domain, Melanie Y. Pullen, Conrad C. Weihl, Heather L. True

Open Access Publications

The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 …

Campylobacter Colonization, Environmental Enteric Dysfunction, Stunting, And Associated Risk Factors Among Young Children In Rural Ethiopia: A Cross-Sectional Study From The Campylobacter Genomics And Environmental Enteric Dysfunction (Caged) Project, Dehao Chen, Mark J Manary, Et Al

Open Access Publications

Livestock farming provides a possible mechanism by which smallholder farmers can meet their household need for animal source foods (ASF), which may reduce the risk of stunting. However, direct/indirect contacts with domestic animals may increase colonization by

Cd4 Inhibits Helper T Cell Activation At Lower Affinity Threshold For Full-Length T Cell Receptors Than Single Chain Signaling Constructs, Deborah K Johnson, Wyatt Magoffin, Sheldon J Myers, Jordan G Finnell, John C Hancock, Taylor S Orton, Stephen P Persaud, Kenneth A Christensen, K Scott Weber

Open Access Publications

CD4

Nonmicrobial Activation Of Tlrs Controls Intestinal Growth, Wound Repair, And Radioprotection, William F Stenson, Matthew A Ciorba

Open Access Publications

TLRs, key components of the innate immune system, recognize microbial molecules. However, TLRs also recognize some nonmicrobial molecules. In particular, TLR2 and TLR4 recognize hyaluronic acid, a glycosaminoglycan in the extracellular matrix. In neonatal mice endogenous hyaluronic acid binding to TLR4 drives normal intestinal growth. Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE

Regulatory T Cells Developing Peri-Weaning Are Continually Required To Restrain Th2 Systemic Responses Later In Life, Kathryn A. Knoop, Keely G Mcdonald, Chyi-Song Hsieh, Phillip I Tarr, Rodney D Newberry

Open Access Publications

Atopic disorders including allergic rhinitis, asthma, food allergy, and dermatitis, are increasingly prevalent in Western societies. These disorders are largely characterized by T helper type 2 (Th2) immune responses to environmental triggers, particularly inhaled and dietary allergens. Exposure to such stimuli during early childhood reduces the frequency of allergies in at-risk children. These allergic responses can be restrained by regulatory T cells (Tregs), particularly Tregs arising in the gut. The unique attributes of how early life exposure to diet and microbes shape the intestinal Treg population is a topic of significant interest. While imprinting during early life promotes the development …

Advances In Modeling The Immune Microenvironment Of Colorectal Cancer, Paul Sukwoo Yoon, Nuala Del Piccolo, Venktesh S Shirure, Yushuan Peng, Amanda Kirane, Robert J Canter, Ryan C Fields, Steven C George, Sepideh Gholami

Open Access Publications

Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment-including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature-are …

Targeting The Tumor Core: Hypoxia-Responsive Nanoparticles For The Delivery Of Chemotherapy To Pancreatic Tumors, Matthew I. Confeld, Babak Mamnoon, Li Feng, Heather Jensen Smith, Priyanka Ray, James Froberg, Jiha Kim, Michael A. Hollingsworth, Mohiuddin Quadir, Yongki Choi, Sanku Mallik

Journal Articles: Eppley Institute

In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to …

The Vimentin Rod Domain Blocks P-Selectin-P-Selectin Glycoprotein Ligand 1 Interactions To Attenuate Leukocyte Adhesion To Inflamed Endothelium, Fong Wilson Lam, Cameron August Brown, Christian Valladolid, Dabel Cynthia Emebo, Timothy Gerald Palzkill, Miguel Angel Cruz

Faculty, Staff and Students Publications

Acute inflammation begins with leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) binding to P-selectin on inflamed endothelium and platelets. In pathologic conditions, this process may contribute to secondary organ damage, like sepsis-induced liver injury. Therefore, developing novel therapies to attenuate inflammation may be beneficial. We previously reported that recombinant human vimentin (rhVim) binds P-selectin to block leukocyte adhesion to endothelium and platelets. In this study, we used SPOT-peptide arrays to identify the rod domain as the active region within rhVim that interacts with P-selectin. Indeed, recombinant human rod domain of vimentin (rhRod) binds to P-selectin with high affinity, with in silico modeling …

Extracellular Mitochondria Released From Traumatized Brains Induced Platelet Procoagulant Activity, Zilong Zhao, Yuan Zhou, Tristan Hilton, Fanjian Li, Cha Han, Li Liu, Hengjie Yuan, Ying Li, Xin Xu, Xiaoping Wu, Fangyi Zhang, Perumal Thiagarajan, Andrew Cap, Fu-Dong Shi, Jianning Zhang, Jing-Fei Dong

Faculty, Staff and Students Publications

Coagulopathy often develops soon after acute traumatic brain injury and its cause remains poorly understood. We have shown that injured brains release cellular microvesicles that disrupt the endothelial barrier and induce consumptive coagulopathy. Morphologically intact extracellular mitochondria accounted for 55.2% of these microvesicles, leading to the hypothesis that these extracellular mitochondria are metabolically active and serve as a source of oxidative stress that activates platelets and renders them procoagulant. In testing this hypothesis experimentally, we found that the extracellular mitochondria purified from brain trauma mice and those released from brains subjected to freeze-thaw injury remained metabolically active and produced reactive …

Protein And Polysaccharide-Based Magnetic Composite Materials For Medical Applications., Elizabeth J Bealer, Kyril Kavetsky, Sierra Dutko, Samuel Lofland, Xiao Hu

College of Science & Mathematics Departmental Research

The combination of protein and polysaccharides with magnetic materials has been implemented in biomedical applications for decades. Proteins such as silk, collagen, and elastin and polysaccharides such as chitosan, cellulose, and alginate have been heavily used in composite biomaterials. The wide diversity in the structure of the materials including their primary monomer/amino acid sequences allow for tunable properties. Various types of these composites are highly regarded due to their biocompatible, thermal, and mechanical properties while retaining their biological characteristics. This review provides information on protein and polysaccharide materials combined with magnetic elements in the biomedical space showcasing the materials used, …

Overview Of Chinese Biodiversity Observation Network (Sino Bon), Feng Xiaojuan, Mi Xiangcheng, Xiao Zhishu, Cao Lei, Wu Hui, Ma Keping

Bulletin of Chinese Academy of Sciences (Chinese Version)

Biodiversity is key to the foundation and development of human society. Biodiversity monitoring and research provide essential scientific support for the national development of ecological civilization and for building a beautiful China. To monitor the dynamic distribution of important species in typical ecoregions of China, Chinese Biodiversity Observation Network (Sino BON) was founded in 2013 under the supports of 19 institutes of the Chinese Academy of Sciences and the sponsorship of the 12th and 13th FiveYear Plans. Covering 30 main sites and 60 affiliated sites all over China, Sino BON includes 10 subnetworks specialized at monitoring different groups of species …

Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson

Faculty Publications

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for …

The Role Of Glia In Epilepsy, Intellectual Disability, And Other Neurodevelopmental Disorders In Tuberous Sclerosis Complex, Michael Wong

Open Access Publications

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, …

Regional Gene Repression By Dna Double-Strand Breaks In G1 Phase Cells, Caitlin E. Purman, Patrick L. Collins, Sofia I. Porter, Ankita Saini, Harshath Gupta, Barry P. Sleckman, Eugene M. Oltz

Open Access Publications

DNA damage responses (DDR) to double-strand breaks (DSBs) alter cellular transcription programs at the genome-wide level. Through processes that are less well understood, DSBs also alter transcriptional responses locally, which may be important for efficient DSB repair. Here, we developed an approach to elucidate the

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …

Ultrafast Two-Photon Imaging Of A High-Gain Voltage Indicator In Awake Behaving Mice, Vincent Villette, Mariya Chavarha, Ivan K Dimov, Jonathan Bradley, Lagnajeet Pradhan, Benjamin Mathieu, Stephen W Evans, Simon Chamberland, Dongqing Shi, Renzhi Yang, Benjamin B Kim, Annick Ayon, Abdelali Jalil, François St-Pierre, Mark J Schnitzer, Guoqiang Bi, Katalin Toth, Jun Ding, Stéphane Dieudonné, Michael Z Lin

Faculty, Staff and Students Publications

Optical interrogation of voltage in deep brain locations with cellular resolution would be immensely useful for understanding how neuronal circuits process information. Here, we report ASAP3, a genetically encoded voltage indicator with 51% fluorescence modulation by physiological voltages, submillisecond activation kinetics, and full responsivity under two-photon excitation. We also introduce an ultrafast local volume excitation (ULoVE) method for kilohertz-rate two-photon sampling in vivo with increased stability and sensitivity. Combining a soma-targeted ASAP3 variant and ULoVE, we show single-trial tracking of spikes and subthreshold events for minutes in deep locations, with subcellular resolution and with repeated sampling over days. In the …