WashU weekly Neuroscience publications

Molecular and mechanical signals determine morphogenesis of the cerebral hemispheres in the chicken embryo
(2019) Development (Cambridge, England), 146 (20), . 

Garcia, K.E.^a , Stewart, W.G.^b , Espinosa, M.G.^c , Gleghorn, J.P.^b , Taber, L.A.^c

^a Department of Biomedical Engineering, Washington University, 1 Brookings Drive, St. Louis, MO 63130, USA karagarc@iu.edu
^b Department of Biomedical Engineering, University of Delaware, 150 Academy Street, Newark, DE 19716, USA
^c Department of Biomedical Engineering, Washington University, 1 Brookings Drive, St. Louis, MO 63130, USA

Abstract
During embryonic development, the telecephalon undergoes extensive growth and cleaves into right and left cerebral hemispheres. Although molecular signals have been implicated in this process and linked to congenital abnormalities, few studies have examined the role of mechanical forces. In this study, we quantified morphology, cell proliferation and tissue growth in the forebrain of chicken embryos during Hamburger-Hamilton stages 17-21. By altering embryonic cerebrospinal fluid pressure during development, we found that neuroepithelial growth depends on not only chemical morphogen gradients but also mechanical feedback. Using these data, as well as published information on morphogen activity, we developed a chemomechanical growth law to mathematically describe growth of the neuroepithelium. Finally, we constructed a three-dimensional computational model based on these laws, with all parameters based on experimental data. The resulting model predicts forebrain shapes consistent with observations in normal embryos, as well as observations under chemical or mechanical perturbation. These results suggest that molecular and mechanical signals play important roles in early forebrain morphogenesis and may contribute to the development of congenital malformations. © 2019. Published by The Company of Biologists Ltd.

Author Keywords
Biomechanics;  Brain development;  Chick;  Finite element model;  Growth law;  Mechanobiology

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

AEBP1 down regulation induced cell death pathway depends on PTEN status of glioma cells
(2019) Scientific Reports, 9 (1), p. 14577. 

Sinha, S.^a , Renganathan, A.^{a b} , Nagendra, P.B.^{a c} , Bhat, V.^{a d} , Mathew, B.S.^a , Rao, M.R.S.^a

^a Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advance Scientific Research, BangaloreKarnataka 560064, India
^b Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA
^c Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
^d Department of Immunology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

Abstract
Glioblastoma (GBM) is the most common aggressive form of brain cancer with overall dismal prognosis (10-12 months) despite all current multimodal treatments. Previously we identified adipocyte enhancer binding protein 1 (AEBP1) as a differentially regulated gene in GBM. On probing the role of AEBP1 over expression in glioblastoma, we found that both cellular proliferation and survival were affected upon AEBP1 silencing in glioma cells, resulting in cell death. In the present study we report that the classical caspase pathway components are not activated in cell death induced by AEBP1 down regulation in PTEN-deficient (U87MG and U138MG) cells. PARP-1 was not cleaved but over-activated under AEBP1 down regulation which leads to the synthesis of PAR in the nucleus triggering the release of AIF from the mitochondria. Subsequently, AIF translocates to the nucleus along with MIF causing chromatinolysis. AEBP1 positively regulates PI3KinaseCβ by the binding to AE-1 binding element in the PI3KinaseCβ promoter. Loss of PI3KinaseCβ expression under AEBP1 depleted condition leads to excessive DNA damage and activation of PARP-1. Furthermore, over expression of PIK3CB (in trans) in U138MG cells prevents DNA damage in these AEBP1 depleted cells. On the contrary, AEBP1 down regulation induces caspase-dependent cell death in PTEN-proficient (LN18 and LN229) cells. Ectopic expression of wild-type PTEN in PTEN-deficient U138MG cells results in the activation of canonical caspase and Akt dependent cell death. Collectively, our findings define AEBP1 as a potential oncogenic driver in glioma, with potential implications for therapeutic intervention.

Document Type: Article
Publication Stage: Final
Source: Scopus

To each, his/her own
(2019) Neuro-Oncology, 21 (10), pp. 1217-1218. 

Rubin, J.B.^a , Schlaggar, B.L.^b

^a Departments of Pediatrics and Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^b Kennedy Krieger Institute and Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia
(2019) Neuro-Oncology, 21 (10), pp. 1250-1262. 

Guo, X., Pan, Y., Gutmann, D.H.

Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
BACKGROUND: One of the clinical hallmarks of low-grade gliomas (LGGs) arising in children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is significant clinical variability with respect to tumor growth, associated neurologic deficits, and response to therapy. Numerous factors could contribute to this clinical heterogeneity, including the tumor cell of origin, the specific germline NF1 gene mutation, and the coexistence of additional genomic alterations. Since human specimens are rarely acquired, and have proven difficult to maintain in vitro or as xenografts in vivo, we have developed a series of Nf1 mutant optic glioma mouse strains representing each of these contributing factors. METHODS: Optic glioma stem cells (o-GSCs) were generated from this collection of Nf1 genetically engineered mice, and analyzed for their intrinsic growth properties, as well as the production of chemokines that could differentially attract T cells and microglia. RESULTS: The observed differences in Nf1 optic glioma growth are not the result of cell autonomous growth properties of o-GSCs, but rather the unique patterns of o-GSC chemokine expression, which differentially attract T cells and microglia. This immune profile collectively dictates the levels of chemokine C-C ligand 5 (Ccl5) expression, the key stromal factor that drives murine Nf1 optic glioma growth. CONCLUSIONS: These findings reveal that genetic and genomic alterations create murine LGG biological heterogeneity through the differential recruitment of T cells and microglia by o-GSC-produced chemokines, which ultimately determine the expression of stromal factors that drive tumor growth. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
chemokine;  glioma stem cells;  precision oncology;  tumor microenvironment

Document Type: Article
Publication Stage: Final
Source: Scopus

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
(2019) Nature Communications, 10 (1), p. 4558. 

Nievergelt, C.M.^{a b c} , Maihofer, A.X.^{a b c} , Klengel, T.^{d e f} , Atkinson, E.G.^{g h} , Chen, C.-Y.^{g h i} , Choi, K.W.^{g j k} , Coleman, J.R.I.^{l m} , Dalvie, S.ⁿ , Duncan, L.E.^o , Gelernter, J.^{p q r} , Levey, D.F.^{r s} , Logue, M.W.^t , Polimanti, R.^{r s} , Provost, A.C.^u , Ratanatharathorn, A.^k , Stein, M.B.^{a v w} , Torres, K.^{a b c} , Aiello, A.E.^x , Almli, L.M.^y , Amstadter, A.B.^z , Andersen, S.B.^aa , Andreassen, O.A.^ab , Arbisi, P.A.^ac , Ashley-Koch, A.E.^ad , Austin, S.B.^{d ae af ag} , Avdibegovic, E.^ah , Babić, D.^ai , Bækvad-Hansen, M.^{aj ak} , Baker, D.G.^{a b w} , Beckham, J.C.^{al am an} , Bierut, L.J.^ao , Bisson, J.I.^ap , Boks, M.P.^aq , Bolger, E.A.^{d e} , Børglum, A.D.^{ak ar as} , Bradley, B.^{y at} , Brashear, M.^au , Breen, G.^{l m} , Bryant, R.A.^av , Bustamante, A.C.^aw , Bybjerg-Grauholm, J.^{aj ak} , Calabrese, J.R.^ax , Caldas-de-Almeida, J.M.^ay , Dale, A.M.^az , Daly, M.J.ⁱ , Daskalakis, N.P.^{d e u ba} , Deckert, J.^bb , Delahanty, D.L.^{bc bd} , Dennis, M.F.^{al am an} , Disner, S.G.^be , Domschke, K.^{bf bg} , Dzubur-Kulenovic, A.^bh , Erbes, C.R.^{bi bj} , Evans, A.^bk , Farrer, L.A.^bl , Feeny, N.C.^bm , Flory, J.D.^ba , Forbes, D.^bn , Franz, C.E.^a , Galea, S.^bo , Garrett, M.E.^am , Gelaye, B.^k , Geuze, E.^{bp bq} , Gillespie, C.^y , Uka, A.G.^br , Gordon, S.D.^bs , Guffanti, G.^{d e} , Hammamieh, R.^bt , Harnal, S.^g , Hauser, M.A.^am , Heath, A.C.^bu , Hemmings, S.M.J.^bv , Hougaard, D.M.^{aj ak} , Jakovljevic, M.^bw , Jett, M.^bt , Johnson, E.O.^bx , Jones, I.^bk , Jovanovic, T.^y , Qin, X.-J.^ad , Junglen, A.G.^bc , Karstoft, K.-I.^{aa by} , Kaufman, M.L.^{d e} , Kessler, R.C.^d , Khan, A.^{e bz} , Kimbrel, N.A.^{ad al an} , King, A.P.^ca , Koen, N.ⁿ , Kranzler, H.R.^{cb cc} , Kremen, W.S.^{a b} , Lawford, B.R.^{cd ce} , Lebois, L.A.M.^{d e} , Lewis, C.E.^bk , Linnstaedt, S.D.^cf , Lori, A.^cg , Lugonja, B.^bk , Luykx, J.J.^{aq bq} , Lyons, M.J.^ch , Maples-Keller, J.^y , Marmar, C.^ci , Martin, A.R.^{g h} , Martin, N.G.^bs , Maurer, D.^cj , Mavissakalian, M.R.^ax , McFarlane, A.^ck , McGlinchey, R.E.^cl , McLaughlin, K.A.^cm , McLean, S.A.^{cf cn} , McLeay, S.^co , Mehta, D.^{cd cp} , Milberg, W.P.^cl , Miller, M.W.^t , Morey, R.A.^ad , Morris, C.P.^{cd ce} , Mors, O.^{ak cq} , Mortensen, P.B.^{ak ar cr cs} , Neale, B.M.^{g h} , Nelson, E.C.^ao , Nordentoft, M.^{ak ct} , Norman, S.B.^{a cu cv} , O’Donnell, M.^bn , Orcutt, H.K.^cw , Panizzon, M.S.^a , Peters, E.S.^au , Peterson, A.L.^cx , Peverill, M.^cy , Pietrzak, R.H.^{s cz} , Polusny, M.A.^{bi da db} , Rice, J.P.^ao , Ripke, S.^{g i dc} , Risbrough, V.B.^{a b c} , Roberts, A.L.^dd , Rothbaum, A.O.^bm , Rothbaum, B.O.^y , Roy-Byrne, P.^cy , Ruggiero, K.^de , Rung, A.^au , Rutten, B.P.F.^df , Saccone, N.L.^ao , Sanchez, S.E.^dg , Schijven, D.^{aq bq} , Seedat, S.^bv , Seligowski, A.V.^{d e} , Seng, J.S.^dh , Sheerin, C.M.^z , Silove, D.^di , Smith, A.K.^{y cg} , Smoller, J.W.^{g h j} , Sponheim, S.R.^{ac bi} , Stein, D.J.ⁿ , Stevens, J.S.^y , Sumner, J.A.^dj , Teicher, M.H.^{d e} , Thompson, W.K.^{a ak dk dl} , Trapido, E.^au , Uddin, M.^dm , Ursano, R.J.^dn , van den Heuvel, L.L.^bv , Van Hooff, M.^ck , Vermetten, E.^{ci do dp dq} , Vinkers, C.H.^{dr ds} , Voisey, J.^{cd ce} , Wang, Y.^{ak dk dl} , Wang, Z.^{dt du} , Werge, T.^{ak dk dv} , Williams, M.A.^k , Williamson, D.E.^{al am} , Winternitz, S.^{d e} , Wolf, C.^bb , Wolf, E.J.^t , Wolff, J.D.^e , Yehuda, R.^{ba dw} , Young, R.M.^{cd cp} , Young, K.A.^{dx dy} , Zhao, H.^dz , Zoellner, L.A.^ea , Liberzon, I.^ca , Ressler, K.J.^{d e y} , Haas, M.^u , Koenen, K.C.^{g i eb}

^a University of California San Diego, Department of Psychiatry, La Jolla, CA, United States
^b Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA
^c Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA
^d Harvard Medical School, Department of Psychiatry, MA, Boston, United States
^e McLean Hospital, MA, Belmont, United States
^f University Medical Center Goettingen, Department of Psychiatry, Göttingen, DE, Germany
^g Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, MA, Cambridge, United States
^h Massachusetts General Hospital, Analytic and Translational Genetics Unit, MA, Boston, United States
ⁱ Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), MA, Boston, United States
^j Massachusetts General Hospital, Department of Psychiatry, MA, Boston, United States
^k Harvard T.H. Chan School of Public Health, Department of Epidemiology, MA, Boston, United States
^l King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, United States
^m King’s College London, London, United States
ⁿ University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town, Western Cape, United States
^o Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, CA, USA
^p US Department of Veterans Affairs, Department of Psychiatry, CT, West Haven, United States
^q Yale University School of Medicine, Department of Genetics and Neuroscience, CT, New Haven, United States
^r VA Connecticut Healthcare Center, CT, West Haven, United States
^s Yale University School of Medicine, Department of Psychiatry, CT, New Haven, United States
^t VA Boston Healthcare System, National Center for PTSD, MA, Boston, United States
^u Cohen Veterans Bioscience, MA, Cambridge, United States
^v Veterans Affairs San Diego Healthcare System, Million Veteran Program, San Diego, CA, USA
^w Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA
^x Gillings School of Global Public Health, Department of Epidemiology, Chapel Hill, United States
^y Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, United States
^z Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, VA, Richmond, United States
^aa Danish Veteran Centre, Research and Knowledge Centre, Ringsted, Denmark
^ab University of Oslo, Institute of Clinical Medicine, NOOslo, Norway
^ac Minneapolis VA Health Care System, Mental Health Service Line, MN, Minneapolis, United States
^ad Duke University, Duke Molecular Physiology Institute, Durham, United States
^ae Boston Children’s Hospital, Division of Adolescent and Young Adult Medicine, MA, Boston, United States
^af Brigham and Women’s Hospital, Channing Division of Network Medicine, MA, Boston, United States
^ag Department of Social and Behavioral Sciences, MA, Harvard School of Public Health, Boston, United States
^ah University Clinical Center of Tuzla, Department of Psychiatry, Tuzla, BA, Bosnia and Herzegovina
^ai University Clinical Center of Mostar, Department of Psychiatry, Mostar, BA, Bosnia and Herzegovina
^aj Statens Serum Institut, Department for Congenital Disorders, Copenhagen, Denmark
^ak Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark
^al Durham VA Medical Center, Research, Durham, United States
^am Duke University, Department of Psychiatry and Behavioral Sciences, Durham, United States
^an VA Mid-Atlantic Mental Illness Research, Education, Clinical Center (MIRECC), Genetics Research Laboratory, Durham, United States
^ao Washington University in Saint Louis School of Medicine, Department of Psychiatry, MO, Saint Louis, United States
^ap Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff, United Kingdom
^aq UMC Utrecht Brain Center Rudolf Magnus, Department of Translational NeuroscienceUtrecht, Netherlands
^ar Aarhus University, Centre for Integrative Sequencing, iSEQ, Aarhus, Denmark
^as Aarhus University, Department of Biomedicine – Human Genetics, Aarhus, Denmark
^at Atlanta VA Health Care System, Mental Health Service Line, Decatur, United States
^au Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology, LA, New Orleans, United States
^av University of New South Wales, Department of Psychology, NSW, Sydney, Australia
^aw University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, MI, Ann Arbor, United States
^ax University Hospitals, Department of Psychiatry, Cleveland, OH, USA
^ay CEDOC -Chronic Diseases Research Centre, Lisbon Institute of Global Mental Health, PTLisbon, Portugal
^az University of California San Diego, Department of Radiology, Department of Neurosciences, La Jolla, CA, United States
^ba Icahn School of Medicine at Mount Sinai, Department of Psychiatry, NY, NY, United States
^bb University Hospital of Würzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, Würzburg, DE, Germany
^bc Kent State University, Department of Psychological Sciences, Kent, OH, USA
^bd Kent State University, Research and Sponsored Programs, Kent, OH, USA
^be Minneapolis VA Health Care System, Research Service Line, MN, Minneapolis, United States
^bf Medical Center-University of Freiburg, Faculty of Medicine, Department of Psychiatry and Psychotherapy, Freiburg, DE, Germany
^bg University of Freiburg, Faculty of Medicine, Centre for Basics in Neuromodulation, Freiburg, DE, Germany
^bh University Clinical Center of Sarajevo, Department of Psychiatry, Sarajevo, BA, Bosnia and Herzegovina
^bi University of Minnesota, Department of Psychiatry, MN, Minneapolis, United States
^bj Minneapolis VA Health Care System, Center for Care Delivery and Outcomes Research (CCDOR), MN, Minneapolis, United States
^bk Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, South Glamorgan, Cardiff, United States
^bl Boston University School of Medicine, Department of Medicine, MA, Boston, United States
^bm Case Western Reserve University, Department of Psychological Sciences, Cleveland, OH, USA
^bn University of Melbourne, Department of Psychiatry, Melbourne, VIC, AU, USA
^bo Boston University, Department of Psychological and Brain Sciences, MA, Boston, United States
^bp Netherlands Ministry of Defence, Brain Research and Innovation CentreUtrecht, Netherlands
^bq UMC Utrecht Brain Center Rudolf Magnus, Department of PsychiatryUtrecht, Netherlands
^br University Clinical Centre of Kosovo, Department of Psychiatry, Prishtina, Kosovo, United States
^bs QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, QLD, Australia
^bt US Army Medical Research and Materiel Command, USACEHR, MD, Fort Detrick, United States
^bu Washington University in Saint Louis School of Medicine, Department of Genetics, MO, Saint Louis, United States
^bv Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town, Western Cape, South Africa
^bw University Hospital Center of Zagreb, Department of Psychiatry, Zagreb, United States
^bx RTI International, Behavioral Health and Criminal Justice Division, Research Triangle Park, United States
^by University of Copenhagen, Department of Psychology, Copenhagen, Denmark
^bz Harvard Medical School, Department of Health Care Policy, MA, Boston, United States
^ca University of Michigan Medical School, Department of Psychiatry, MI, Ann Arbor, United States
^cb University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, United States
^cc Mental Illness Research, Education and Clinical Center, Philadelphia, United States
^cd Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove, AU, Australia
^ce Queensland University of Technology, School of Biomedical Sciences, Kelvin Grove, AU, Australia
^cf Department of Anesthesiology, Chapel Hill, United States
^cg Emory University, Department of Gynecology and Obstetrics, Atlanta, United States
^ch Boston University, Dean’s Office, MA, Boston, United States
^ci New York University School of Medicine, Department of Psychiatry, NY, NY, United States
^cj United States Army, United States
^ck University of Adelaide, Department of Psychiatry, Adelaide, South Australia, AU, Australia
^cl VA Boston Health Care System, MA, Boston, United States
^cm Harvard University, Department of Psychology, MA, Boston, United States
^cn Department of Emergency Medicine, Chapel Hill, United States
^co Gallipoli Medical Research Institute, AU, QLD, Australia
^cp Queensland University of Technology, School of Psychology and Counseling, Faculty of Health, Kelvin Grove, AU, Australia
^cq Aarhus University Hospital, Psychosis Research Unit, Denmark
^cr Aarhus University, Centre for Integrated Register-based Research, Aarhus, Denmark
^cs Aarhus University, National Centre for Register-Based Research, Aarhus, Denmark
^ct University of Copenhagen, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, Copenhagen, Denmark
^cu Veterans Affairs San Diego Healthcare System, Department of Research and Psychiatry, San Diego, CA, USA
^cv Executive Division, White River Junction, VT, National Center for Post Traumatic Stress Disorder, San Diego, United States
^cw Northern Illinois University, Department of Psychology, DeKalb, United States
^cx University of Texas Health Science Center at San Antonio, Department of Psychiatry, TX, San Antonio, United States
^cy University of Washington, Department of Psychology, Seattle, WA, USA
^cz U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, CT, West Haven, United States
^da Minneapolis VA Health Care System, Department of Mental Health, MN, Minneapolis, United States
^db Minneapolis VA Health Care System, Department of Psychology, MN, Minneapolis, United States
^dc Charité – Universitätsmedizin, Department of Psychiatry and Psychotherapy, GEBerlin, Germany
^dd Harvard T.H. Chan School of Public Health, Department of Environmental Health, MA, Boston, United States
^de Medical University of South Carolina, Department of Nursing and Department of Psychiatry, SC, Charleston, United States
^df Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht, Limburg, Netherlands
^dg Universidad Peruana de Ciencias Aplicadas Facultad de Ciencias de la Salud, Department of Medicine, PELima, United States
^dh University of Michigan, School of Nursing, MI, Ann Arbor, United States
^di University of New South Wales, Department of Psychiatry, Sydney, NSW, AU, USA
^dj Columbia University Medical Center, Department of Medicine, NY, NY, United States
^dk Mental Health Centre Sct. Hans, Institute of Biological Psychiatry, Roskilde, Denmark
^dl Oslo University Hospital, KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, NOOslo, United States
^dm University of South Florida College of Public Health, Genomics Program, FL, Tampa, United States
^dn Uniformed Services University, Department of Psychiatry, Bethesda, MD, United States
^do Arq, Psychotrauma Reseach Expert Group, NH, Diemen, Netherlands
^dp Leiden University Medical Center, Department of Psychiatry, Leiden, Netherlands
^dq Netherlands Defense Department, Research Center, UTUtrecht, Netherlands
^dr Department of Anatomy and Neurosciences, Amsterdam, Netherlands
^ds Department of Psychiatry, Amsterdam, Netherlands
^dt Ralph H Johnson VA Medical Center, Department of Mental Health, SC, Charleston, United States
^du Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, SC, Charleston, United States
^dv University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark
^dw James J Peters VA Medical Center, Department of Mental Health, Bronx, NY, USA
^dx Baylor Scott and White Central Texas, Department of Psychiatry, TX, Temple, United States
^dy COE for Research on Returning War Veterans, TX, Waco, United States
^dz Yale University, Department of Biostatistics, CT, New Haven, United States
^ea University of Washington, Department of Psychiatry and Behavioral Sciences, Seattle, WA, USA
^eb Department of Epidemiology, MA, Harvard School of Public Health, Boston, United States

Abstract
The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Dosing interval of natalizumab in MS: Do good things come to those who wait?
(2019) Neurology, 93 (15), pp. 655-656. 

Clifford, D.B., Tyler, K.L.

From the Department of Neurology (D.B.C.), Washington University in St Louis, MO; and Department of Medicine and Immunology-Microbiology (K.L.T.), University of Colorado School of Medicine, Aurora

Document Type: Editorial
Publication Stage: Final
Source: Scopus

Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells
(2019) Science Immunology, 4 (40), . 

Wang, Q.^a , Robinette, M.L.^a , Billon, C.^b , Collins, P.L.^c , Bando, J.K.^a , Fachi, J.L.^{a d} , Sécca, C.^a , Porter, S.I.^c , Saini, A.^c , Gilfillan, S.^a , Solt, L.A.^e , Musiek, E.S.^f , Oltz, E.M.^c , Burris, T.P.^b , Colonna, M.^a

^a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA
^c Department of Microbial Infection and Immunity, Ohio State University College of Medicine, Columbus, OH 43210, USA
^d Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
^e Department of Immunology and Microbiology, Scripps Research Institute, Jupiter, FL 33458, United States
^f Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA

Abstract
Many gut functions are attuned to circadian rhythm. Intestinal group 3 innate lymphoid cells (ILC3s) include NKp46+ and NKp46- subsets, which are RORγt dependent and provide mucosal defense through secretion of interleukin-22 (IL-22) and IL-17. Because ILC3s highly express some key circadian clock genes, we investigated whether ILC3s are also attuned to circadian rhythm. We noted circadian oscillations in the expression of clock and cytokine genes, such as REV-ERBα, IL-22, and IL-17, whereas acute disruption of the circadian rhythm affected cytokine secretion by ILC3s. Because of prominent and rhythmic expression of REV-ERBα in ILC3s, we also investigated the impact of constitutive deletion of REV-ERBα, which has been previously shown to inhibit the expression of a RORγt repressor, NFIL3, while also directly antagonizing DNA binding of RORγt. Development of the NKp46+ ILC3 subset was markedly impaired, with reduced cell numbers, RORγt expression, and IL-22 production in REV-ERBα-deficient mice. The NKp46- ILC3 subsets developed normally, potentially due to compensatory expression of other clock genes, but IL-17 secretion paradoxically increased, probably because RORγt was not antagonized by REV-ERBα. We conclude that ILC3s are attuned to circadian rhythm, but clock regulator REV-ERBα also has circadian-independent impacts on ILC3 development and functions due to its roles in the regulation of RORγt. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Postintensive Care Syndrome in Pediatric Critical Care Survivors: Therapeutic Options to Improve Outcomes After Acquired Brain Injury
(2019) Current Treatment Options in Neurology, 21 (10), art. no. 49, . 

Williams, C.N.^{a b} , Hartman, M.E.^c , Guilliams, K.P.^{c d} , Guerriero, R.M.^d , Piantino, J.A.^{a e} , Bosworth, C.C.^f , Leonard, S.S.^g , Bradbury, K.^g , Wagner, A.^g , Hall, T.A.^{a g g}

^a Pediatric Critical Care and Neurotrauma Recovery Program, Oregon Health and Science University, 707 SW Gaines St., CDRC-P, Portland, OR 97239, United States
^b Department of Pediatrics, Division of Pediatric Critical Care, Oregon Health and Science University, Portland, OR, United States
^c Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
^d Department of Neurology, Division of Pediatric and Developmental Neurology, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
^e Department of Pediatrics, Division of Pediatric Neurology, Oregon Health and Science University, Portland, OR, United States
^f Department of Psychology, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
^g Department of Pediatrics, Division of Pediatric Psychology, Oregon Health and Science University, Portland, OR, United States

Abstract
Purpose of review: Children surviving the pediatric intensive care unit (PICU) with neurologic illness or injury have long-term morbidities in physical, cognitive, emotional, and social functioning termed postintensive care syndrome (PICS). In this article, we review acute and longitudinal management strategies available to combat PICS in children with acquired brain injury. Recent findings: Few intervention studies in this vulnerable population target PICS morbidities. Small studies show promise for both inpatient- and outpatient-initiated therapies, mainly focusing on a single domain of PICS and evaluating heterogeneous populations. While evaluating the effects of interventions on longitudinal PICS outcomes is in its infancy, longitudinal clinical programs targeting PICS are increasing. A multidisciplinary team with inpatient and outpatient presence is necessary to deliver the holistic integrated care required to address all domains of PICS in patients and families. Summary: While PICS is increasingly recognized as a chronic problem in PICU survivors with acquired brain injury, few interventions have targeted PICS morbidities. Research is needed to improve physical, cognitive, emotional, and social outcomes in survivors and their families. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Brain injury;  Critical care;  Outcomes;  Pediatric;  Stroke

Document Type: Review
Publication Stage: Final
Source: Scopus

Sodium-activated potassium channels moderate excitability in vascular smooth muscle
(2019) The Journal of Physiology, 597 (20), pp. 5093-5108. 

Li, P.^a , Halabi, C.M.^b , Stewart, R.^a , Butler, A.^a , Brown, B.^a , Xia, X.^c , Santi, C.^{a d} , England, S.^d , Ferreira, J.^{a d} , Mecham, R.P.^e , Salkoff, L.^{a f}

^a Department of Neuroscience
^b Department of Pediatrics
^c Department of Anesthesiology
^d Department of Obstetrics and Gynecology
^e Department of Cell Biology and Physiology
^f Department of Genetics, Washington University School of Medicine, MO, Saint Louis, United States

Abstract
KEY POINTS: We report that a sodium-activated potassium current, IKNa , has been inadvertently overlooked in both conduit and resistance arterial smooth muscle cells. IKNa is a major K+ resting conductance and is absent in cells of IKNa knockout (KO) mice. The phenotype of the IKNa KO is mild hypertension, although KO mice react more strongly than wild-type with raised blood pressure when challenged with vasoconstrictive agents. IKNa is negatively regulated by angiotensin II acting through Gαq protein-coupled receptors. In current clamp, KO arterial smooth muscle cells have easily evoked Ca2+ -dependent action potentials. ABSTRACT: Although several potassium currents have been reported to play a role in arterial smooth muscle (ASM), we find that one of the largest contributors to membrane conductance in both conduit and resistance ASMs has been inadvertently overlooked. In the present study, we show that IKNa , a sodium-activated potassium current, contributes a major portion of macroscopic outward current in a critical physiological voltage range that determines intrinsic cell excitability; IKNa is the largest contributor to ASM cell resting conductance. A genetic knockout (KO) mouse strain lacking KNa channels (KCNT1 and KCNT2) shows only a modest hypertensive phenotype. However, acute administration of vasoconstrictive agents such as angiotensin II (Ang II) and phenylephrine results in an abnormally large increase in blood pressure in the KO animals. In wild-type animals Ang II acting through Gαq protein-coupled receptors down-regulates IKNa , which increases the excitability of the ASMs. The complete genetic removal of IKNa in KO mice makes the mutant animal more vulnerable to vasoconstrictive agents, thus producing a paroxysmal-hypertensive phenotype. This may result from the lowering of cell resting K+ conductance allowing the cells to depolarize more readily to a variety of excitable stimuli. Thus, the sodium-activated potassium current may serve to moderate blood pressure in instances of heightened stress. IKNa may represent a new therapeutic target for hypertension and stroke. © 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.

Author Keywords
angiotensin II;  KNa1.1;  KNa1.2;  persistent sodium current;  potassium channel;  Slo1;  Slo2.1;  vascular smooth muscle

Document Type: Article
Publication Stage: Final
Source: Scopus

Response to commentary on recommendations for the use of structural MRI in the care of patients with epilepsy: A consensus report from the ILAE Neuroimaging Task Force
(2019) Epilepsia, 60 (10), pp. 2143-2144. 

Bernasconi, A.^a , Cendes, F.^b , Theodore, W.^c , Gill, R.S.^a , Koepp, M.^d , Hogan, R.E.^e , Jackson, G.^f , Federico, P.^g , Labate, A.^h , Vaudano, A.E.ⁱ , Blümcke, I.^j , Ryvlin, P.^k , Bernasconi, N.^a

^a Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
^b Department of Neurology, University of Campinas-UNICAMP, Campinas, Brazil
^c Clinical Epilepsy Section, NIH, MD, Bethesda, United States
^d Institute for Neurology, University College London, London, United Kingdom
^e Department of Neurology, Washington University Scholl of Medicine, St. Louis, MO, USA
^f University of Melbourne, The Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
^g Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
^h Institute of Neurology, University of Catanzaro, Catanzaro, Italy
ⁱ Neurology Unit, OCASE Hospital, AOU Modena, University of Modena and Reggio-Emilia, Modena, Italy
^j Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
^k Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland

Document Type: Letter
Publication Stage: Final
Source: Scopus

Maintenance of Melanocyte Stem Cell Quiescence by GABA-A Signaling in Larval Zebrafish
(2019) Genetics, 213 (2), pp. 555-566. 

Allen, J.R.^a , Skeath, J.B.^a , Johnson, S.L.^b

^a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
In larval zebrafish, melanocyte stem cells (MSCs) are quiescent, but can be recruited to regenerate the larval pigment pattern following melanocyte ablation. Through pharmacological experiments, we found that inhibition of γ-aminobutyric acid (GABA)-A receptor function, specifically the GABA-A ρ subtype, induces excessive melanocyte production in larval zebrafish. Conversely, pharmacological activation of GABA-A inhibited melanocyte regeneration. We used clustered regularly interspaced short palindromic repeats/Cas9 to generate two mutant alleles of gabrr1, a subtype of GABA-A receptors. Both alleles exhibited robust melanocyte overproduction, while conditional overexpression of gabrr1 inhibited larval melanocyte regeneration. Our data suggest that gabrr1 signaling is necessary to maintain MSC quiescence and sufficient to reduce, but not eliminate, melanocyte regeneration in larval zebrafish. Copyright © 2019 by the Genetics Society of America.

Author Keywords
CRISPR;  GABA;  GABA-A receptors;  inhibition;  melanocyte;  pigmentation;  quiescence;  zebrafish

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Primary Spinal Cord Glioblastoma Multiforme in the Young and Old
(2019) Neurohospitalist, 9 (4), pp. 243-244. 

Rodriguez, J.^a , Dionne, K.^b , Wu, G.F.^b , Goyal, M.S.^c , Bucelli, R.C.^b

^a Washington University School of Medicine, St Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neurology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States

Author Keywords
brain neoplasms;  clinical specialty;  clinical specialty;  nervous system neoplasms;  nervous system neoplasms;  neurooncology;  neuroradiology;  spinal cord compression;  spinal cord diseases;  spinal cord neoplasms

Document Type: Note
Publication Stage: Final
Source: Scopus

Oculopalatal Tremor Following Pontine Hemorrhage
(2019) Neurohospitalist, 9 (4), pp. 241-242. 

Wilks, A.^a , McCullough, A.^b , Day, G.S.^{a c}

^a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States

Author Keywords
Guillain-Mollaret triangle;  hypertrophic olivary degeneration;  oculopalatal tremor;  pendular nystagmus

Document Type: Note
Publication Stage: Final
Source: Scopus

A Neurobehavioral Approach to Addiction: Implications for the Opioid Epidemic and the Psychology of Addiction
(2019) Psychological Science in the Public Interest : a Journal of the American Psychological Society, 20 (2), pp. 96-127. 

Bechara, A.^{a b} , Berridge, K.C.^c , Bickel, W.K.^d , Morón, J.A.^{e f} , Williams, S.B.^{e f} , Stein, J.S.^d

^a Department of Psychology, University of Southern California
^b Brain and Creativity Institute, University of Southern California
^c Department of Psychology, University of Michigan
^d Addiction Recovery Research Center & Center for Transformational Research on Health Behaviors, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA, United States
^e Department of Anesthesiology, Washington University School of Medicine
^f Washington University Pain Center, Washington University School of Medicine

Abstract
Two major questions about addictive behaviors need to be explained by any worthwhile neurobiological theory. First, why do people seek drugs in the first place? Second, why do some people who use drugs seem to eventually become unable to resist drug temptation and so become “addicted”? We will review the theories of addiction that address negative-reinforcement views of drug use (i.e., taking opioids to alleviate distress or withdrawal), positive-reinforcement views (i.e., taking drugs for euphoria), habit views (i.e., growth of automatic drug-use routines), incentive-sensitization views (i.e., growth of excessive “wanting” to take drugs as a result of dopamine-related sensitization), and cognitive-dysfunction views (i.e., impaired prefrontal top-down control), including those involving competing neurobehavioral decision systems (CNDS), and the role of the insula in modulating addictive drug craving. In the special case of opioids, particular attention is paid to whether their analgesic effects overlap with their reinforcing effects and whether the perceived low risk of taking legal medicinal opioids, which are often prescribed by a health professional, could play a role in the decision to use. Specifically, we will address the issue of predisposition or vulnerability to becoming addicted to drugs (i.e., the question of why some people who experiment with drugs develop an addiction, while others do not). Finally, we review attempts to develop novel therapeutic strategies and policy ideas that could help prevent opioid and other substance abuse.

Author Keywords
decision making;  incentive sensitization;  insula;  opioid abuse

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Changes in Metabolic Parameters and Body Weight in Patients With Major Depressive Disorder Treated With Adjunctive Brexpiprazole: Pooled Analysis of Phase 3 Clinical Studies
(2019) The Journal of Clinical Psychiatry, 80 (6), . 

Newcomer, J.W.^{a b c} , Eriksson, H.^d , Zhang, P.^e , Meehan, S.R.^d , Weiss, C.^e

^a 7205 Corporate Center Dr, FL 33126, Thriving Mind South FloridaSte 200, Miami, United States
^b Thriving Mind South Florida, Miami, FL, United States
^c Washington University School of Medicine, St Louis, MO, United States
^d H. Lundbeck A/S, Copenhagen, Denmark
^e Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, NJ, United States

Abstract
OBJECTIVE: To analyze the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with major depressive disorder (MDD) based on pooled data from 4 short-term studies and 1 long-term extension study. METHODS: The short-term studies (June 2011 to November 2016) were randomized, double-blind, placebo-controlled studies in outpatients with MDD (DSM-IV-TR criteria) and inadequate response to 1-3 prior antidepressant treatments (ADTs) plus 1 prospective ADT. Patients were randomized to adjunctive brexpiprazole (fixed or flexible doses in the range of 1-3 mg/d; n = 1,032) or placebo (n = 819) for 6 weeks. The long-term study (October 2011 to May 2017) was a 52-week (amended to 26 weeks), open-label, uncontrolled study of adjunctive brexpiprazole 0.5-3 mg/d (flexible dose; n = 2,938). Mean changes from baseline and categorical shifts in fasting metabolic parameters (cholesterol, triglycerides, and glucose) and body weight were analyzed. RESULTS: Mean changes from baseline in metabolic parameters were small after 6 weeks (all < 2 mg/dL) and 52 weeks (all < 4 mg/dL, except triglycerides, 15.83 mg/dL) of treatment. In most cases, the incidence of unfavorable shifts in metabolic parameters was lower than the incidence of favorable shifts. Mean body weight increase at last visit in the short-term studies was 1.5 kg with ADT + brexpiprazole and 0.3 kg with ADT + placebo. During long-term treatment, mean body weight increased by 3.8 kg over 58 weeks. CONCLUSIONS: Adjunctive brexpiprazole was associated with small changes in metabolic parameters and moderate weight gain during short- and long-term treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT01360866. © Copyright 2019 Physicians Postgraduate Press, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Measuring Diurnal Rhythms in Autophagic and Proteasomal Flux
(2019) Journal of Visualized Experiments : JoVE, (151), . 

Ryzhikov, M.^a , Eubanks, A.^a , Haspel, J.A.^b

^a Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine
^b Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine;

Abstract
Cells employ several methods for recycling unwanted proteins and other material, including lysosomal and non-lysosomal pathways. The main lysosome-dependent pathway is called autophagy, while the primary non-lysosomal method for protein catabolism is the ubiquitin-proteasome system. Recent studies in model organisms suggest that the activity of both autophagy and the ubiquitin-proteasome system is not constant across the day but instead varies according to a daily (circadian) rhythm. The ability to measure biological rhythms in protein turnover is important for understanding how cellular quality control is achieved and for understanding the dynamics of specific proteins of interest. Here we present a standardized protocol for quantifying autophagic and proteasomal flux in vivo that captures the circadian component of protein turnover. Our protocol includes details for mouse handling, tissue processing, fractionation, and autophagic flux quantification using mouse liver as the starting material.

Document Type: Article
Publication Stage: Final
Source: Scopus

An Open-Source, Automated Home-Cage Sipper Device for Monitoring Liquid Ingestive Behavior in Rodents
(2019) eNeuro, 6 (5), . 

Godynyuk, E.^a , Bluitt, M.N.^b , Tooley, J.R.^a , Kravitz, A.V.^{a b c} , Creed, M.C.^{a b c}

^a Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63108, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63108, United States
^c Departments of Neuroscience and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63108, United States

Abstract
Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput experiments; and (4) it is open source so that others can modify it to fit their experimental needs. We validated the performance of this device in three experiments. First, we calibrated our device using time-lapse video-based measurements of liquid intake and correlated sipper interactions with liquid intake. Second, we used the sipper device to measure preference for water versus chocolate milk, demonstrating its utility for two-bottle choice tasks. Third, we integrated the device with fiber photometry, establishing its utility for measuring neural activity in studies of ingestive behavior. This device requires no special equipment or caging, and is small, battery powered, and wireless, allowing it to be placed directly in rodent home cages. The total cost of fabrication is less than $100, and all design files and code are open source. Together, these factors greatly increase scalability and utility for a variety of behavioral neuroscience applications. Copyright © 2019 Godynyuk et al.

Author Keywords
Arduino;  open source hardware;  two-bottle choice

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Shared autonomic pathways connect bone marrow and peripheral adipose tissues across the central neuraxis
(2019) Frontiers in Endocrinology, 10 (SEP), art. no. 668, . 

Wee, N.K.Y.^{a b} , Lorenz, M.R.^a , Bekirov, Y.^a , Jacquin, M.F.^c , Scheller, E.L.^{a d}

^a Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Reconstructive Sciences, UConn Health, Farmington, CT, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Bone marrow adipose tissue (BMAT) is increased in both obesity and anorexia. This is unique relative to white adipose tissue (WAT), which is generally more attuned to metabolic demand. It suggests that there may be regulatory pathways that are common to both BMAT and WAT and also those that are specific to BMAT alone. The central nervous system (CNS) is a key mediator of adipose tissue function through sympathetic adrenergic neurons. Thus, we hypothesized that central autonomic pathways may be involved in BMAT regulation. To test this, we first quantified the innervation of BMAT by tyrosine hydroxylase (TH) positive nerves within the metaphysis and diaphysis of the tibia of B6 and C3H mice. We found that many of the TH+ axons were concentrated around central blood vessels in the bone marrow. However, there were also areas of free nerve endings which terminated in regions of BMAT adipocytes. Overall, the proportion of nerve-associated BMAT adipocytes increased from proximal to distal along the length of the tibia (from ∼3–5 to ∼14–24%), regardless of mouse strain. To identify the central pathways involved in BMAT innervation and compare to peripheral WAT, we then performed retrograde viral tract tracing with an attenuated pseudorabies virus (PRV) to infect efferent nerves from the tibial metaphysis (inclusive of BMAT) and inguinal WAT (iWAT) of C3H mice. PRV positive neurons were identified consistently from both injection sites in the intermediolateral horn of the spinal cord, reticular formation, rostroventral medulla, solitary tract, periaqueductal gray, locus coeruleus, subcoeruleus, Barrington’s nucleus, and hypothalamus. We also observed dual-PRV infected neurons within the majority of these regions. Similar tracings were observed in pons, midbrain, and hypothalamic regions from B6 femur and tibia, demonstrating that these results persist across mouse strains and between skeletal sites. Altogether, this is the first quantitative report of BMAT autonomic innervation and reveals common central neuroanatomic pathways, including putative “command” neurons, involved in coordinating multiple aspects of sympathetic output and facilitation of parallel processing between bone marrow/BMAT and peripheral adipose tissue. © 2019 Wee, Lorenz, Bekirov, Jacquin and Scheller.

Author Keywords
Autonomic nervous system;  Bone marrow adipose tissue;  Brain-bone interactions;  Energy metabolism;  Fat;  Pseudorabies virus;  Sympathetic nerve;  Viral tract tracing

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

An Integrative Model of Personality Disorder: Part 3: Mechanism-Based Approach to the Pharmacotherapy of Personality Disorder: An Emerging Concept
(2019) Psychiatria Danubina, 31 (3), pp. 290-307. 

Svrakic, D., Mofsen, A., Chockalingam, R., Divac-Jovanovic, M., Zorumski, C.F.

Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, United States

Abstract
Temperament traits of Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence, are well defined in terms of their neural circuitry, neurochemical modulators, and patterns of associative learning. When heritably excessive, each of these traits may become a mechanistically fundamental biogenetic trait vulnerability for personality disorder. The other main risk factor for personality disorder is environmental, notably abuse, neglect, and psychological trauma. The emerging concept of mechanism-based pharmacotherapy aims to activate the brain’s homeostasis as the only available delivery system to re-calibrate complex neurophysiological participants in each of the temperament traits. In a positive feedback, a homeostasis-driven improvement of excessive temperament is expected to facilitate maturation of neocortical networks of cognition, most reliably in expert psychotherapy (Part I of this paper) and, ultimately, thereby improve top-down cortical control of subcortical affect reactivity. As an emerging concept informed by neuroscience and clinical research, mechanism-based pharmacotherapy has the potential to be superior to traditional symptom-based treatments. Such mechanism-based approach illustrates what the pharmacological treatment of Research Domain Criteria (RDoC) might look like.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Strain variations in cone wavelength peaks in situ during zebrafish development
(2019) Visual Neuroscience, 36, p. E010. 

Nelson, R.F.^a , Balraj, A.^{a b} , Suresh, T.^{a c} , Torvund, M.^{a d} , Patterson, S.S.^{a e}

^a Neural Circuitry Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, MD, United States
^b Department of Anatomy and Biology, George Washington University, Washington, District of Columbia
^c Department of Biology, Washington University, St Louis, MO, United States
^d Neurobiology, University of Arizona, Tucson, AZ, United States
^e Neuroscience Graduate Program, Department of Ophthalmology, University of Washington, Seattle, WA, United States

Abstract
There are four cone morphologies in zebrafish, corresponding to UV (U), blue (B), green (G), and red (R)-sensing types; yet genetically, eight cone opsins are expressed. How eight opsins are physiologically siloed in four cone types is not well understood, and in larvae, cone physiological spectral peaks are unstudied. We use a spectral model to infer cone wavelength peaks, semisaturation irradiances, and saturation amplitudes from electroretinogram (ERG) datasets composed of multi-wavelength, multi-irradiance, aspartate-isolated, cone-PIII signals, as compiled from many 5- to 12-day larvae and 8- to 18-month-old adult eyes isolated from wild-type (WT) or roy orbison (roy) strains. Analysis suggests (in nm) a seven-cone, U-360/B1-427/B2-440/G1-460/G3-476/R1-575/R2-556, spectral physiology in WT larvae but a six-cone, U-349/B1-414/G3-483/G4-495/R1-572/R2-556, structure in WT adults. In roy larvae, there is a five-cone structure: U-373/B2-440/G1-460/R1-575/R2-556; in roy adults, there is a four-cone structure, B1-410/G3-482/R1-571/R2-556. Existence of multiple B, G, and R types is inferred from shifts in peaks with red or blue backgrounds. Cones were either high or low semisaturation types. The more sensitive, low semisaturation types included U, B1, and G1 cones [3.0-3.6 log(quanta·μm-2·s-1)]. The less sensitive, high semisaturation types were B2, G3, G4, R1, and R2 types [4.3-4.7 log(quanta·μm-2·s-1)]. In both WT and roy, U- and B- cone saturation amplitudes were greater in larvae than in adults, while G-cone saturation levels were greater in adults. R-cone saturation amplitudes were the largest (50-60% of maximal dataset amplitudes) and constant throughout development. WT and roy larvae differed in cone signal levels, with lesser UV- and greater G-cone amplitudes occurring in roy, indicating strain variation in physiological development of cone signals. These physiological measures of cone types suggest chromatic processing in zebrafish involves at least four to seven spectral signal processing pools.

Author Keywords
Adaptation pools;  Hill function;  Interference filter;  Microelectrode;  Nonlinear curve fit;  Origin LabTalk;  Patch electrode;  Selective chromatic adaptation;  Spectral sensitivity;  Xenon arc

Document Type: Article
Publication Stage: Final
Source: Scopus

Microglia as Dynamic Cellular Mediators of Brain Function
(2019) Trends in Molecular Medicine, . 

Wright-Jin, E.C., Gutmann, D.H.

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Originally hypothesized to function solely as immunologic responders within the central nervous system (CNS), emerging evidence has revealed that microglia have more complex roles in normal brain development and in the context of disease. In health, microglia influence neural progenitor fate decisions, astrocyte activation, neuronal homeostasis, and synaptogenesis. In the setting of brain disease, including autism, brain tumors, and neurodegenerative disorders, microglia undergo substantial morphological, molecular, and functional changes, which establish new biological states relevant to disease pathogenesis and progression. In this review, we discuss the function of microglia in health and disease and outline a conceptual framework for elucidating their specific contributions to nervous system pathobiology. © 2019 Elsevier Ltd

Author Keywords
brain;  central nervous system;  glioma;  macrophage;  microglia;  precision medicine

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

Protocol for the electroencephalography guidance of anesthesia to alleviate geriatric syndromes (ENGAGES-Canada) study: A pragmatic, randomized clinical trial
(2019) F1000Research, 8, p. 1165. 

Deschamps, A.^a , Saha, T.^b , El-Gabalawy, R.^c , Jacobsohn, E.^d , Overbeek, C.^e , Palermo, J.^e , Robichaud, S.^f , Dumont, A.A.^g , Djaiani, G.^h , Carroll, J.^h , Kavosh, M.S.ⁱ , Tanzola, R.^b , Schmitt, E.M.^j , Inouye, S.K.^j , Oberhaus, J.^k , Mickle, A.^k , Ben Abdallah, A.^k , Avidan, M.S.^k , Clinical Trials Group, C.P.A.^l

^a Department of Anesthesiology and Pain Medicine, Montreal Heart Institute and Universite de Montreal, Montreal, QC H1T 1C8, Canada
^b Department of Anesthesiology and Perioperative Medicine, Queen’s University, Kingston, Kingston, Ontario, Canada
^c Department of Clinical Health Psychology, Anesthesiology, Perioperative and Pain Medicine, University of Manitoba, Winnipeg, MB, Canada
^d Departments of Anesthesia and Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
^e Department of Anesthesiology and Pain Medicine, University of Montreal, Montreal, QC, Canada
^f Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
^g Montreal Health Innovation Coordinating Center, Montreal Heart Institute, Montreal, QC, Canada
^h Department of Anesthesia, University of Toronto, Toronto, ON, Canada
ⁱ Department of Anesthesiology, Perioperative and Pain Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
^j Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States
^k Department of Anesthesiology, Washington University School of MedicineMO, United States
^l Department of Anesthesia, University of Manitoba, Winnipeg, MB, Canada

Abstract
Background:  There is some evidence that electroencephalography guidance of general anesthesia can decrease postoperative delirium after non-cardiac surgery.  There is limited evidence in this regard for cardiac surgery.  A suppressed electroencephalogram pattern, occurring with deep anesthesia, is associated with increased incidence of postoperative delirium (POD) and death.  However, it is not yet clear whether this electroencephalographic pattern reflects an underlying vulnerability associated with increased incidence of delirium and mortality, or whether it is a modifiable risk factor for these adverse outcomes. Methods:  The Electroe ncephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes ( ENGAGES-Canada) is an ongoing pragmatic 1200 patient trial at four Canadian sites.  The study compares the effect of two anesthetic management approaches on the incidence of POD after cardiac surgery.  One approach is based on current standard anesthetic practice and the other on electroencephalography guidance to reduce POD. In the guided arm, clinicians are encouraged to decrease anesthetic administration, primarily if there is electroencephalogram suppression and secondarily if the EEG index is lower than the manufacturers recommended value (bispectral index (BIS) or WAVcns below 40 or Patient State Index below 25).  The aim in the guided group is to administer the minimum concentration of anesthetic considered safe for individual patients.  The primary outcome of the study is the incidence of POD, detected using the confusion assessment method or the confusion assessment method for the intensive care unit; coupled with structured delirium chart review.  Secondary outcomes include unexpected intraoperative movement, awareness, length of intensive care unit and hospital stay, delirium severity and duration, quality of life, falls, and predictors and outcomes of perioperative distress and dissociation. Discussion:  The ENGAGES-Canada trial will help to clarify whether or not using the electroencephalogram to guide anesthetic administration during cardiac surgery decreases the incidence, severity, and duration of POD. Registration: ClinicalTrials.gov ( NCT02692300) 26/02/2016. Copyright: © 2019 Deschamps A et al.

Author Keywords
anesthetic management;  cardiac surgery;  cardiopulmonary bypass;  EEG suppression;  geriatric outcomes;  perioperative risk factors;  postoperative delirium;  volatile anesthetics

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Using deep-learning to predict outcome of patients with Parkinson’s disease
(2018) 2018 IEEE Nuclear Science Symposium and Medical Imaging Conference, NSS/MIC 2018 – Proceedings, art. no. 8824432, . Cited 1 time.

Leung, K.H.^a , Salmanpour, M.R.^b , Saberi, A.^c , Klyuzhin, I.S.^d , Sossi, V.^d , Jha, A.K.^e , Pomper, M.G.^a , Du, Y.^a , Rahmim, A.^d

^a Johns Hopkins University, Baltimore, MD, United States
^b Amirkabir University of Technology, Tehran, Iran
^c Islamic Azad University, Tehran, Iran
^d University of British Columbia, Vancouver, BC, Canada
^e Washington University in St. Louis, St. Louis, MO, United States

Abstract
There are currently no established disease modifying therapies for PD, and prediction of outcome in PD to power clinical studies is a very important area of research. Assessment of PD is informed by imaging the dopamine system with dopamine transporter (DAT) single-photon emission computed tomography (SPECT) imaging and by the presence of key symptoms. Recently, deep-learning based methods have shown promise for medical image analysis tasks and disease detection. The purpose of this study was to develop a deep-learning based approach to predict outcome of patients with PD using longitudinal clinical data containing imaging and non-imaging information. Features were first extracted from the clinical data by the proposed deep-learning based approach and then combined to predict motor performance (MDS-UPDRS-III) in year 4. The performance of the proposed approach was evaluated via a 10-fold cross-validation. We evaluated the performance of the network on the basis of mean absolute error (MAE) between the predicted and true MDS-UPDRS part III scores in year 4. The proposed approach yielded a MAE of 4.33±3.36 when given only imaging features, 3.71±2.91 when given only non-imaging features, and 3.22±2.71 when given all input data. While the approach given only non-imaging input data outperformed the approach given only imaging data, we found that the performance of the proposed approach substantially improved when given both imaging and non-imaging information. Our results indicate that the addition of imaging data to non-imaging clinical data is helpful for the prediction of outcome in patients with PD. The proposed approach that incorporated both imaging and non-imaging clinical data shows significant promise for prediction of outcome in patients with PD. © 2018 IEEE.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus