Publications

Hope Center member publications

List of publications for the week of October 18, 2021

Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids” (2021) Nature Communications

Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids
(2021) Nature Communications, 12 (1), art. no. 5763, . 

Jones, J.R.a b , Chaturvedi, S.a , Granados-Fuentes, D.a , Herzog, E.D.a

a Department of Biology, Washington University, St. Louis, St. Louis, MO, United States
b Department of Biology, Texas A&M University, College Station, College Station, TX, United States

Abstract
Signals from the central circadian pacemaker, the suprachiasmatic nucleus (SCN), must be decoded to generate daily rhythms in hormone release. Here, we hypothesized that the SCN entrains rhythms in the paraventricular nucleus (PVN) to time the daily release of corticosterone. In vivo recording revealed a critical circuit from SCN vasoactive intestinal peptide (SCNVIP)-producing neurons to PVN corticotropin-releasing hormone (PVNCRH)-producing neurons. PVNCRH neurons peak in clock gene expression around midday and in calcium activity about three hours later. Loss of the clock gene Bmal1 in CRH neurons results in arrhythmic PVNCRH calcium activity and dramatically reduces the amplitude and precision of daily corticosterone release. SCNVIP activation reduces (and inactivation increases) corticosterone release and PVNCRH calcium activity, and daily SCNVIP activation entrains PVN clock gene rhythms by inhibiting PVNCRH neurons. We conclude that daily corticosterone release depends on coordinated clock gene and neuronal activity rhythms in both SCNVIP and PVNCRH neurons. © 2021, The Author(s).

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIF32 HL133772
National Institute of General Medical SciencesNIGMSR01GM131403

Document Type: Article
Publication Stage: Final
Source: Scopus

CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum” (2021) Nature Communications

CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
(2021) Nature Communications, 12 (1), art. no. 5702, . 

Reddy, N.C.a , Majidi, S.P.a b , Kong, L.a , Nemera, M.a , Ferguson, C.J.a , Moore, M.a , Goncalves, T.M.a , Liu, H.-K.c , Fitzpatrick, J.A.J.a d e f , Zhao, G.a , Yamada, T.a g , Bonni, A.a , Gabel, H.W.a

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b MD-PhD Program, Washington University School of Medicine, St. Louis, MO 63110, United States
c Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance, German Cancer Research Center Im Neunheimer Feld 280, Heidelberg, 69120, Germany
d Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
f Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Neurobiology, Northwestern University, Evanston, IL 60201, United States

Abstract
Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes chromatin accessibility, active histone modifications, and RNA polymerase recruitment at enhancers. In vivo profiling of genome architecture reveals that CHD7 concordantly regulates epigenomic modifications associated with enhancer activation and gene expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a potential cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define epigenomic regulation by CHD7 in granule cell precursors and identify abnormal cerebellar patterning upon CHD7 depletion, with potential implications for our understanding of CHARGE syndrome. © 2021, The Author(s).

Funding details
CDI-CORE-2015-505, CDI-CORE-2019-813, OD021694
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSNS041021
G. Harold and Leila Y. Mathers Charitable Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Levels of circulating NS1 impact West Nile virus spread to the brain” (2021) Journal of Virology

Levels of circulating NS1 impact West Nile virus spread to the brain
(2021) Journal of Virology, 95 (20), art. no. e00844-21, . 

Wessel, A.W.a b , Dowd, K.A.c , Biering, S.B.d , Zhang, P.e , Edeling, M.A.a , Nelson, C.A.a , Funk, K.E.b , DeMaso, C.R.c , Klein, R.S.a b f g , Smith, J.L.h i , Cao, T.M.j k , Kuhn, R.J.j k , Fremont, D.H.a l m , Harris, E.d , Pierson, T.C.c , Diamond, M.S.a b l n

a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Viral Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
d Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
e Department of Immunology, Key Laboratory of Tropical Diseases Control, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
g Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
h Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
i Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, United States
j Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
k Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN, United States
l Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
m Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
n Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Dengue virus (DENV) and West Nile virus (WNV) are arthropod-transmitted flaviviruses that cause systemic vascular leakage and encephalitis syndromes, respectively, in humans. However, the viral factors contributing to these specific clinical disorders are not completely understood. Flavivirus nonstructural protein 1 (NS1) is required for replication, expressed on the cell surface, and secreted as a soluble glycoprotein, reaching high levels in the blood of infected individuals. Extracellular DENV NS1 and WNV NS1 interact with host proteins and cells, have immune evasion functions, and promote endothelial dysfunction in a tissue-specific manner. To characterize how differences in DENV NS1 and WNV NS1 might function in pathogenesis, we generated WNV NS1 variants with substitutions corresponding to residues found in DENV NS1. We discovered that the substitution NS1-P101K led to reduced WNV infectivity in the brain and attenuated lethality in infected mice, although the virus replicated efficiently in cell culture and peripheral organs and bound at wild-type levels to brain endothelial cells and complement components. The P101K substitution resulted in reduced NS1 antigenemia in mice, and this was associated with reduced WNV spread to the brain. Because exogenous administration of NS1 protein rescued WNV brain infectivity in mice, we conclude that circulating WNV NS1 facilitates viral dissemination into the central nervous system and impacts disease outcomes. IMPORTANCE Flavivirus NS1 serves as an essential scaffolding molecule during virus replication but also is expressed on the cell surface and is secreted as a soluble glycoprotein that circulates in the blood of infected individuals. Although extracellular forms of NS1 are implicated in immune modulation and in promoting endothelial dysfunction at blood-tissue barriers, it has been challenging to study specific effects of NS1 on pathogenesis without disrupting its key role in virus replication. Here, we assessed WNV NS1 variants that do not affect virus replication and evaluated their effects on pathogenesis in mice. Our characterization of WNV NS1-P101K suggests that the levels of NS1 in the circulation facilitate WNV dissemination to the brain and affect disease outcomes. Our findings facilitate understanding of the role of NS1 during flavivirus infection and support antiviral strategies for targeting circulating forms of NS1. © 2021 American Society for Microbiology. All Rights Reserved.

Author Keywords
Animal model;  Dissemination;  Endothelial cells;  Flavivirus;  Viral pathogenesis;  Virology

Funding details
National Institutes of HealthNIH75N93019C00062, HHSN272201400058C, R01 AI073755, R01 AI124493, T32 5T32AI007172-38
National Institute of Allergy and Infectious DiseasesNIAID

Document Type: Article
Publication Stage: Final
Source: Scopus

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases” (2021) Frontiers in Neurology

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases
(2021) Frontiers in Neurology, 12, art. no. 700714, . 

Scorr, L.M.a , Factor, S.A.a , Parra, S.P.a , Kaye, R.b , Paniello, R.C.c , Norris, S.A.c , Perlmutter, J.S.c , Bäumer, T.d , Usnich, T.d , Berman, B.D.e , Mailly, M.f , Roze, E.g , Vidailhet, M.g , Jankovic, J.h , LeDoux, M.S.i j , Barbano, R.k , Chang, F.C.F.l , Fung, V.S.C.l , Pirio Richardson, S.m , Blitzer, A.n , Jinnah, H.A.a , for the Dystonia Coalition Investigatorso

a Department of Neurology, Emory University, Atlanta, GA, United States
b Department of Otolaryngology, Rutgers University, Newark, NJ, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Institute of Systems Motor Science, Universität of Lübeck, Lübeck, Germany
e Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
f Department of ENT and Head and Neck Surgery, Fondation Adolphe de Rothschild, Paris, France
g Department of Neurology, Hôpital de la Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France
h Baylor St. Luke’s Medical Center, Houston, TX, United States
i Veracity Neuroscience LLC, Memphis, TN, United States
j Department of Neurology, University of Memphis, Memphis, TN, United States
k Department of Neurology, University of Rochester, Rochester, NY, United States
l Department of Neurology, Westmead Hospital, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
m Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
n Head and Neck Surgical Group, New York, NY, United States

Abstract
Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies. © Copyright © 2021 Scorr, Factor, Parra, Kaye, Paniello, Norris, Perlmutter, Bäumer, Usnich, Berman, Mailly, Roze, Vidailhet, Jankovic, LeDoux, Barbano, Chang, Fung, Pirio Richardson, Blitzer and Jinnah.

Author Keywords
botulinum (neuro)toxin;  dystonia;  jaw;  tongue;  treatment

Document Type: Article
Publication Stage: Final
Source: Scopus

Information content differentiates enhancers from silencers in mouse photoreceptors” (2021) eLife

Information content differentiates enhancers from silencers in mouse photoreceptors
(2021) eLife, 10, art. no. e67403, . 

Friedman, R.Z.a , Granas, D.M.a , Myers, C.A.b , Corbo, J.C.b , Cohen, B.A.a , White, M.A.a

a Edison Family Center for Genome Sciences and Systems Biology, and Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state. To identify sequence features that distinguish enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF CRX in mouse retinas. Both enhancers and silencers contain more TF motifs than inactive sequences, but relative to silencers, enhancers contain motifs from a more diverse collection of TFs. We developed a measure of information content that describes the number and diversity of motifs in a sequence and found that, while both enhancers and silencers depend on CRX motifs, enhancers have higher information content. The ability of information content to distinguish enhancers and silencers targeted by the same TF illustrates how motif context determines the activity of cis-regulatory sequences. © 2021, eLife Sciences Publications Ltd. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping” (2021) Journal of the Royal Society, Interface

Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping
(2021) Journal of the Royal Society, Interface, 18 (182), p. 20210454. 

Sueviriyapan, N.a , Granados-Fuentes, D.b , Simon, T.b , Herzog, E.D.b , Henson, M.A.a

a Department of Chemical Engineering and the Institute for Applied Life Sciences, University of Massachusetts, MA, Amherst, United States
b Department of Biology, Washington University in St Louis, MO, Saint Louis, United States

Abstract
In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABAA receptor subunits, often referred to as synaptic GABAA (gamma subunit) and extra-synaptic GABAA (delta subunit). To test the functional roles of these distinct GABAA in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABAA receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABAA reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABAA densities could enhance synchrony, as opposed to increasing delta GABAA densities. Overall, our model reveals how blocking GABAA receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABAA density in the winter could underlie the tighter phase relationships among SCN cells.

Author Keywords
circadian rhythms;  GABA receptor;  mathematical modelling;  suprachiasmatic nucleus

Document Type: Article
Publication Stage: Final
Source: Scopus

Enhancing Cognition in Older Persons with Depression or Anxiety with a Combination of Mindfulness-Based Stress Reduction (MBSR) and Transcranial Direct Current Stimulation (tDCS): Results of a Pilot Randomized Clinical Trial” (2021) Mindfulness

Enhancing Cognition in Older Persons with Depression or Anxiety with a Combination of Mindfulness-Based Stress Reduction (MBSR) and Transcranial Direct Current Stimulation (tDCS): Results of a Pilot Randomized Clinical Trial
(2021) Mindfulness, . 

Brooks, H.a , Oughli, H.A.b , Kamel, L.b , Subramanian, S.b , Morgan, G.c , Blumberger, D.M.a , Kloeckner, J.b , Kumar, S.a , Mulsant, B.H.a , Lenze, E.J.b , Rajji, T.K.a d

a Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada
b Washington University School of Medicine, St. Louis, MO, United States
c Centre for Mindfulness Studies, Toronto, Canada
d Toronto Dementia Research Alliance, University of Toronto, Toronto, Canada

Abstract
Objectives: Individuals with subjective memory complaints and symptoms of depression and/or anxiety are at high risk for further cognitive decline, and possible progression to dementia. Low-burden interventions to help slow or prevent cognitive decline in this high-risk group are needed. The objective of this study is to assess the feasibility of combining Mindfulness-Based Stress Reduction (MBSR) with transcranial direct current stimulation (tDCS) to increase putative benefits of MBSR for cognitive function and everyday mindfulness in depressed or anxious older adults with subjective cognitive decline. Methods: We conducted a two-site pilot double-blind randomized sham-controlled trial, combining active MBSR with either active or sham tDCS. The intervention included weekly in-class group sessions at the local university hospital and daily at-home practice. Anodal tDCS was applied for 30 min during MBSR meditative practice, both in-class and at-home. Results: Twenty-six individuals with subjective cognitive complaints and symptoms of depression and/or anxiety were randomized to active (n = 12) or sham tDCS (n = 14). The combination of MBSR and tDCS was safe and well tolerated, though at-home adherence and in-class attendance were variable. While they were not statistically significant, the largest effect sizes for active vs. sham tDCS were for everyday mindfulness (d = 0.6) and social functioning (d = 0.9) (F(1,21) = 3.68, p = 0.07 and F(1,21) = 3.9, p = 0.06, respectively). Conclusions: Our findings suggest that it is feasible and safe to combine tDCS with MBSR in older depressed and anxious adults, including during remote, at-home use. Furthermore, tDCS may enhance MBSR via transferring its meditative learning and practice into increases in everyday mindfulness. Future studies need to improve adherence to MBSR with tDCS. Trial Registration: ClinicalTrials.gov (NCT03653351 and NCT03680664). © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Cognitive function;  Late-life anxiety;  Late-life depression;  MBSR;  Mindfulness;  Subjective cognitive complaints;  tDCS

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR25 MH112473
National Institute on AgingNIA
Brain and Behavior Research FoundationBBRF
Eli Lilly and Company
Patient-Centered Outcomes Research InstitutePCORI
BrightFocus FoundationBFF
Evelyn F. McKnight Brain Research FoundationMBRF
Fondation Brain Canada
Acadia University
National Alliance for Research on Schizophrenia and DepressionNARSAD
Weston Brain InstituteWBI
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Centre for Addiction and Mental Health FoundationCAMH
Takeda Canada
Canadian Institutes of Health ResearchIRSC
Canada Foundation for InnovationCFI
Ontario Ministry of Health and Long-Term CareMOHLTC
Canada Research Chairs950–230879
Ontario Ministry of Research, Innovation and ScienceMRIS
University of TorontoU of T
H. Lundbeck A/S

Document Type: Article
Publication Stage: Article in Press
Source: Scopus