Publications

Hope Center Member Publications

Scopus list of publications for November 27, 2022

Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease” (2022) Molecular Therapy – Methods and Clinical Development

Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease
(2022) Molecular Therapy – Methods and Clinical Development, 27, pp. 452-463. 

Pearse, Y.a , Clarke, D.a , Kan, S.-H.a b , Le, S.Q.a , Sanghez, V.a , Luzzi, A.a , Pham, I.c , Nih, L.R.a c d , Cooper, J.D.e , Dickson, P.I.e , Iacovino, M.a f

a Department of Pediatrics, the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, United States
b CHOC Research Institute, Orange, CA 92868, United States
c Department of Neurology, the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, United States
d Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
e Department of Pediatrics, Washington University, Saint Louis, MO 63110, United States
f Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States

Abstract
Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB) is a recessive genetic disorder that severely affects the brain due to a deficiency in the enzyme α-N-acetylglucosaminidase (NAGLU), leading to intra-lysosomal accumulation of partially degraded heparan sulfate. There are no effective treatments for this disorder. In this project, we carried out an ex vivo correction of neural stem cells derived from Naglu−/− mice (iNSCs) induced pluripotent stem cells (iPSC) using a modified enzyme in which human NAGLU is fused to an insulin-like growth factor II receptor binding peptide in order to improve enzyme uptake. After brain transplantation of corrected iNSCs into Naglu−/− mice and long-term evaluation of their impact, we successfully detected NAGLU-IGFII activity in all transplanted animals. We found decreased lysosomal accumulation and reduced astrocytosis and microglial activation throughout transplanted brains. We also identified a novel neuropathological phenotype in untreated Naglu−/− brains with decreased levels of the neuronal marker Map2 and accumulation of synaptophysin-positive aggregates. Upon transplantation, we restored levels of Map2 expression and significantly reduced formation of synaptophysin-positive aggregates. Our findings suggest that genetically engineered iNSCs can be used to effectively deliver the missing enzyme to the brain and treat Sanfilippo type B-associated neuropathology. © 2022

Author Keywords
cell therapy;  LSD;  MPS;  neural progenitor cells;  Sanfilippo type B

Funding details
National Institute of Neurological Disorders and StrokeNINDS1R01 NS088766, 1R41NS092221-0181, 4R33NS096044-03, 5T32 GM8243-28

Document Type: Article
Publication Stage: Final
Source: Scopus

Detection and discrimination of electrical stimuli from an upper limb cuff electrode in M. Mulatta” (2022) Journal of Neural Engineering

Detection and discrimination of electrical stimuli from an upper limb cuff electrode in M. Mulatta
(2022) Journal of Neural Engineering, 19 (6), art. no. 066009, . 

Schlichenmeyer, T.C., Zellmer, E.R., Burton, H., Ray, W.Z., Moran, D.W.

Washington University in St Louis, 1 Brookings Dr, St Louis, MO 63118, United States

Abstract
Objective. Peripheral nerve interfaces seek to restore nervous system function through electrical stimulation of peripheral nerves. In clinical use, these devices should function reliably for years or decades. In this study, we assessed evoked sensations from multi-channel cuff electrode stimulation in macaque monkeys up to 711 d post-implantation. Approach. Three trained macaque monkeys received multi-channel cuff electrode implants at the median or ulnar nerves in the upper arm. Electrical stimuli from the cuff interfaces evoked sensations, which we measured via standard psychophysical tasks. We adjusted pulse amplitude or pulse width for each block with various electrode channel configurations to examine the effects of stimulus parameterization on sensation. We measured detection thresholds and just-noticeable differences (JNDs) at irregular, near-daily intervals for several months using Bayesian inferencing from trial data. We examined data trends using classical models such as Weber’s Law and the strength-duration relationship using linear regression. Main results. Detection thresholds were similar between blocks with pulse width modulation and blocks with pulse amplitude modulation when represented as charge per pulse, the product of the amplitude and the pulse width. Conversely, Weber fractions—calculated as the slope of the regression between JND charge values and reference stimulus charge—were significantly different between pulse width and pulse amplitude modulation blocks for the discrimination task. Significance. Weber fractions were lower in blocks with amplitude modulation than in blocks with pulse width modulation, suggesting that pulse amplitude modulation allows finer resolution of sensory encoding above threshold. Consequently, amplitude modulation may enable a greater dynamic range for sensory perception with neuroprosthetic devices. © 2022 IOP Publishing Ltd.

Author Keywords
neural prosthetics;  peripheral nerve;  psychophysics;  somatosensation

Funding details
HR0011-15-2-0007
Defense Advanced Research Projects AgencyDARPA

Document Type: Article
Publication Stage: Final
Source: Scopus

Myostatin is a negative regulator of adult neurogenesis after spinal cord injury in zebrafish” (2022) Cell Reports

Myostatin is a negative regulator of adult neurogenesis after spinal cord injury in zebrafish
(2022) Cell Reports, 41 (8), art. no. 111705, . 

Saraswathy, V.M.a b , Zhou, L.a b , McAdow, A.R.a b , Burris, B.a b , Dogra, D.c d , Reischauer, S.c e f , Mokalled, M.H.a b

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany
d Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
e Medical Clinic I, (Cardiology/Angiology) and Campus Kerckhoff, Justus Liebig University, Giessen, Giessen, 35392, Germany
f The Cardio-Pulmonary Institute, Frankfurt, Germany

Abstract
Intrinsic and extrinsic inhibition of neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after complete SC transection. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local adult neurogenesis affects functional recovery is unknown. Here, we uncover dynamic expression of zebrafish myostatin b (mstnb) in a niche of dorsal SC progenitors after injury. mstnb mutants show impaired functional recovery, normal glial and axonal bridging across the lesion, and an increase in the profiles of newborn neurons. Molecularly, neuron differentiation genes are upregulated, while the neural stem cell maintenance gene fgf1b is downregulated in mstnb mutants. Finally, we show that human fibroblast growth factor 1 (FGF1) treatment rescues the molecular and cellular phenotypes of mstnb mutants. These studies uncover unanticipated neurogenic functions for mstnb and establish the importance of local adult neurogenesis for innate SC repair. © 2022 The Author(s)

Author Keywords
adult neurogenesis;  CP: Developmental biology;  CP: Neuroscience;  eural stem cells;  myostatin;  neuronal differentiation;  regeneration;  spinal cord injury;  zebrafish

Funding details
National Institutes of HealthNIHR01 NS113915
University of WashingtonUW
National Institutes of Natural SciencesNINS

Document Type: Article
Publication Stage: Final
Source: Scopus

Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid” (2022) Nature

Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid
(2022) Nature, 611 (7936), pp. 585-593. 

Drieu, A.a b , Du, S.a b c , Storck, S.E.a b , Rustenhoven, J.a b , Papadopoulos, Z.a b c , Dykstra, T.a b , Zhong, F.d , Kim, K.a b , Blackburn, S.a b , Mamuladze, T.a b c , Harari, O.e , Karch, C.M.e f , Bateman, R.J.f , Perrin, R.b f , Farlow, M.g , Chhatwal, J.h , Brosch, J.g , Buck, J.g , Farlow, M.g , Ghetti, B.g , Adams, S.i , Barthelemy i, N. , Benzinger, T.i , Brandon, S.i , Buckles, V.i , Cash, L.i , Chen, C.i , Chua, J.i , Cruchaga, C.i , Denner, D.i , Dincer, A.i , Donahue, T.i , Fagan, A.i , Feldman, B.i , Flores, S.i , Franklin, E.i , Joseph-Mathurin, N.i , Gonzalez, A.i , Gordon, B.i , Gray, J.i , Gremminger, E.i , Groves, A.i , Hassenstab, J.i , Hellm, C.i , Herries, E.i , Hoechst-Swisher, L.i , Holtzman, D.i , Hornbeck, R.i , Jerome, G.i , Keefe, S.i , Koudelis, D.i , Li, Y.i , Marsh, J.i , Martinez, R.i , Mawuenyega, K.i , McCullough, A.i , McDade, E.i , Morris, J.i , Norton, J.i , Shady, K.i , Sigurdson, W.i , Smith, J.i , Wang, P.i , Wang, Q.i , Xiong, C.i , Xu, J.i , Xu, X.i , Allegri, R.j , Mendez, P.C.j , Egido, N.j , Araki, A.k , Ikeuchi, T.k , Ishii, K.k l , Kasuga, K.k , Bechara, J.m , Brooks, W.m , Schofield, P.m , Berman, S.n , Goldberg, S.n , Ikonomovic, S.n , Klunk, W.n , Lopez, O.n , Mountz, J.n , Nadkarni, N.n , Patira, R.n , Smith, L.n , Snitz, B.n , Thompson, S.n , Weamer, E.n , Bodge, C.o , Salloway, S.o , Carter, K.p , Duong, D.p , Johnson, E.p , Levey, A.p , Ping, L.p , Seyfried, N.T.p , Fitzpatrick, C.q , Chui, H.r , Ringman, J.r , Day, G.S.s , Graff-Radford, N.s , Graham, M.s , Stephens, S.s , Cruz, C.D.L.t , Goldman, J.t , Mejia, A.t , Neimeyer, K.t , Noble, J.t , Diffenbacher, A.u , Yakushev, I.u , Levin, J.u , Vöglein, J.u , Douglas, J.v , Fox, N.v , Grilo, M.v , Mummery, C.v , O’Connor, A.v , Esposito, B.w , Goate, A.w , Renton, A.w , Fujii, H.x , Senda, M.x , Shimada, H.x , Gardener, S.y , Martins, R.y , Sohrabi, H.y , Taddei, K.y , Gräber-Sultan, S.z , Häsler, L.z , Hofmann, A.z , Jucker, M.z , Käser, S.z , Kuder-Buletta, E.z , Laske, C.z , Preische, O.z , Haass, C.aa , Morenas-Rodriguez, E.aa , Nuscher, B.aa , Ihara, R.l , Nagamatsu, A.l , Niimi, Y.l , Jack, C.ab , Koeppe, R.ac , Mason, N.S.ad , Masters, C.ae , Obermüller, U.af , Hu, S.d , Randolph, G.J.b , Smirnov, I.a b , Kipnis, J.a b c , Dominantly Inherited Alzheimer Networkag

a Center for Brain Immunology and Glia (BIG), Washington University in St Louis, St Louis, MO, United States
b Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
c Immunology Graduate Program, School of Medicine, Washington University in St Louis, St Louis, MO, United States
d Department of Biomedical Engineering, Washington University in St Louis, Danforth Campus, St Louis, MO, United States
e Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
f Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, School of Medicine, Washington University in St Louis, St Louis, MO, United States
g Indiana School of Medicine, Indianapolis, IN, United States
h Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
i School of Medicine, Washington University in St Louis, St Louis, MO, United States
j Institute of Neurological Research Fleni, Buenos Aires, Argentina
k Niigata University, Niigata, Japan
l Tokyo University, Tokyo, Japan
m Neuroscience Research Australia, Sydney, NSW, Australia
n University of Pittsburgh, Pittsburgh, PA, United States
o Brown University–Butler Hospital, Providence, RI, United States
p Emory University School of Medicine, Atlanta, GA, United States
q Brigham and Women’s Hospital–Massachusetts General Hospital, Boston, MA, United States
r University of Southern California, Los Angeles, CA, United States
s Mayo Clinic Jacksonville, Jacksonville, FL, United States
t Columbia University, New York, NY, United States
u German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
v University College London, London, United Kingdom
w Icahn School of Medicine at Mount Sinai, New York, NY, United States
x Osaka City University, Osaka, Japan
y Edith Cowan University, Perth, WA, Australia
z German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany
aa Ludwig–Maximilian’s University, Munich, Germany
ab Mayo Clinic, Rochester, NY, United States
ac University of Michigan, Ann Arbor, MI, United States
ad University of Pittsburgh Medical Center, Pittsburgh, PA, United States
ae University of Melbourne, Parkville, VIC, Australia
af Hertie Institute for Clinical Brain Research, Tubingen, Germany

Abstract
Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer’s disease (AD) and from non-AD individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
AG057777, AG062734, AG067764
National Institutes of HealthNIH
National Institute on AgingNIAAG034113, AG057496, AG078106
National Institute of General Medical SciencesNIGMSP41 GM103422, R24GM136766
National Center for Advancing Translational SciencesNCATSUL1 TR000448
Alzheimer’s Disease Research Center, Emory UniversityADRC
Cure Alzheimer’s FundCAF
University of WashingtonUW
Institute of Clinical and Translational SciencesICTS
University of VirginiaUV
Japan Agency for Medical Research and DevelopmentAMED
Cosmetic Surgery FoundationCSF
Center for Cellular Imaging, Washington UniversityWUCCI
Alvin J. Siteman Cancer CenterNCI P30 CA091842, P01AG026276, P01AG03991, P30 AG066444, UF1AG032438
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGAD
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni

Document Type: Article
Publication Stage: Final
Source: Scopus

The incidence of candidate binding sites for β-arrestin in Drosophila neuropeptide GPCRs” (2022) PLoS ONE

The incidence of candidate binding sites for β-arrestin in Drosophila neuropeptide GPCRs
(2022) PLoS ONE, 17 (11 November), art. no. e0275410, . 

Taghert, P.H.

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

Abstract
To support studies of neuropeptide neuromodulation, I have studied beta-arrestin binding sites (BBS’s) by evaluating the incidence of BBS sequences among the C terminal tails (CTs) of each of the 49 Drosophila melanogaster neuropeptide GPCRs. BBS were identified by matches with a prediction derived from structural analysis of rhodopsin:arrestin and vasopressin receptor: arrestin complexes [1]. To increase the rigor of the identification, I determined the conservation of BBS sequences between two long-diverged species D. melanogaster and D. virilis. There is great diversity in the profile of BBS’s in this group of GPCRs. I present evidence for conserved BBS’s in a majority of the Drosophila neuropeptide GPCRs; notably some have no conserved BBS sequences. In addition, certain GPCRs display numerous conserved compound BBS’s, and many GPCRs display BBS-like sequences in their intracellular loop (ICL) domains as well. Finally, 20 of the neuropeptide GPCRs are expressed as protein isoforms that vary in their CT domains. BBS profiles are typically different across related isoforms suggesting a need to diversify and regulate the extent and nature of GPCR:arrestin interactions. This work provides the initial basis to initiate future in vivo, genetic analyses in Drosophila to evaluate the roles of arrestins in neuropeptide GPCR desensitization, trafficking and signaling. © 2022 Paul H. Taghert. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR01 NS108393-20

Document Type: Article
Publication Stage: Final
Source: Scopus

Stroke genetics informs drug discovery and risk prediction across ancestries” (2022) Nature

Stroke genetics informs drug discovery and risk prediction across ancestries
(2022) Nature, 611 (7934), pp. 115-123. Cited 2 times.

Mishra, A.a , Malik, R.b , Hachiya, T.c , Jürgenson, T.d e , Namba, S.f , Posner, D.C.g , Kamanu, F.K.h i , Koido, M.j k , Le Grand, Q.a , Shi, M.k , He, Y.k , Georgakis, M.K.b l m , Caro, I.a , Krebs, K.d , Liaw, Y.-C.n o , Vaura, F.C.p q , Lin, K.r , Winsvold, B.S.s t u , Srinivasasainagendra, V.v , Parodi, L.l m , Bae, H.-J.w , Chauhan, G.x , Chong, M.R.y z , Tomppo, L.aa , Akinyemi, R.ab ac , Roshchupkin, G.V.ad ae , Habib, N.af , Jee, Y.H.ag , Thomassen, J.Q.ah , Abedi, V.ai aj , Cárcel-Márquez, J.ak al , Nygaard, M.am an , Leonard, H.L.ao ap aq , Yang, C.ar as , Yonova-Doing, E.at au , Knol, M.J.ad , Lewis, A.J.av , Judy, R.L.aw , Ago, T.ax , Amouyel, P.ay az ba , Armstrong, N.D.bb , Bakker, M.K.bc , Bartz, T.M.bd be , Bennett, D.A.bf , Bis, J.C.bd , Bordes, C.a , Børte, S.t bg bh , Cain, A.af , Ridker, P.M.bi bj , Cho, K.g , Chen, Z.r bk , Cruchaga, C.bl bm , Cole, J.W.bn bo , de Jager, P.L.m bp , de Cid, R.bq , Endres, M.br bs bt bu , Ferreira, L.E.bv , Geerlings, M.I.bw , Gasca, N.C.be , Gudnason, V.bx by , Hata, J.bz , He, J.av , Heath, A.K.ca , Ho, Y.-L.g , Havulinna, A.S.cb cc , Hopewell, J.C.cd , Hyacinth, H.I.ce , Inouye, M.at cf cg ch ci , Jacob, M.A.cj , Jeon, C.E.ck , Jern, C.cl cm , Kamouchi, M.cn , Keene, K.L.co , Kitazono, T.ax , Kittner, S.J.bo cp , Konuma, T.f , Kumar, A.x , Lacaze, P.cq , Launer, L.J.cr , Lee, K.-J.cs , Lepik, K.d ct cu cv , Li, J.ai , Li, L.cw , Manichaikul, A.ar , Markus, H.S.cx , Marston, N.A.h i , Meitinger, T.cy cz , Mitchell, B.D.da db , Montellano, F.A.dc dd , Morisaki, T.j , Mosley, T.H.de , Nalls, M.A.ao ap aq , Nordestgaard, B.G.df dg , O’Donnell, M.J.dh , Okada, Y.f di dj dk dl dm , Onland-Moret, N.C.bw , Ovbiagele, B.dn , Peters, A.do dp dq , Psaty, B.M.bd dr ds , Rich, S.S.ar , Rosand, J.l m dt , Sabatine, M.S.h i , Sacco, R.L.du dv , Saleheen, D.dw , Sandset, E.C.dx dy , Salomaa, V.cb , Sargurupremraj, M.dz , Sasaki, M.c , Satizabal, C.L.dz ea , Schmidt, C.O.eb , Shimizu, A.c , Smith, N.L.dr ec ed , Sloane, K.L.ee , Sutoh, Y.c , Sun, Y.V.ef eg , Tanno, K.c , Tiedt, S.b , Tatlisumak, T.eh , Torres-Aguila, N.P.ak , Tiwari, H.K.v , Trégouët, D.-A.a , Trompet, S.ei ej , Tuladhar, A.M.cj , Tybjærg-Hansen, A.ah dg , van Vugt, M.ek , Vibo, R.el , Verma, S.S.em , Wiggins, K.L.bd , Wennberg, P.en , Woo, D.ce , Wilson, P.W.F.ef eo , Xu, H.da , Yang, Q.ea ep , Yoon, K.eq , Millwood, I.Y.r bk , Gieger, C.er , Ninomiya, T.bz , Grabe, H.J.es et , Jukema, J.W.ej eu ev , Rissanen, I.L.bw , Strbian, D.aa , Kim, Y.J.eq , Chen, P.-H.o , Mayerhofer, E.l m , Howson, J.M.M.at au , Irvin, M.R.bb , Adams, H.ew ex , Wassertheil-Smoller, S.ey , Christensen, K.am an ez , Ikram, M.A.ad , Rundek, T.du dv , Worrall, B.B.fa fb , Lathrop, G.M.fc , Riaz, M.cq , Simonsick, E.M.fd , Kõrv, J.el , França, P.H.C.bv , Zand, R.fe ff , Prasad, K.x , Frikke-Schmidt, R.ah dg , de Leeuw, F.-E.cj , Liman, T.bs bw fg , Haeusler, K.G.dd , Ruigrok, Y.M.bc , Heuschmann, P.U.dc fh fi , Longstreth, W.T.dr fj , Jung, K.J.r fk , Bastarache, L.av , Paré, G.y z fl fm , Damrauer, S.M.fn fo , Chasman, D.I.bi bj , Rotter, J.I.fp , Anderson, C.D.l m dt fq , Zwart, J.-A.s t bg , Niiranen, T.J.p q fr , Fornage, M.fs ft , Liaw, Y.-P.o fu , Seshadri, S.dz ea fv , Fernández-Cadenas, I.ak , Walters, R.G.r bk , Ruff, C.T.h i , Owolabi, M.O.ab fw , Huffman, J.E.g , Milani, L.d , Kamatani, Y.k , Dichgans, M.b fx fy , Debette, S.a fz , COMPASS Consortiumga , INVENT Consortiumgb , Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Groupgc , Estonian Biobankgd , PRECISEQ Consortiumge , FinnGen Consortiumgf , NINDS Stroke Genetics Network (SiGN)gg , MEGASTROKE Consortiumgh , SIREN Consortiumgi , China Kadoorie Biobank Collaborative Groupgj , VA Million Veteran Programgk , International Stroke Genetics Consortium (ISGC)gl , Biobank Japangm , CHARGE Consortiumgn , GIGASTROKE Consortiumgo


a Bordeaux Population Health Research Center, University of Bordeaux, Inserm, Bordeaux, France
b Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
c Iwate Tohoku Medical Megabank Organization, Iwate Medical UniversityIwate, Japan
d Estonian Genome Centre, Institute of Genomics, University of TartuTartu, Estonia
e Institute of Mathematics and Statistics, University of TartuTartu, Estonia
f Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
g Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, United States
h TIMI Study Group, Boston, MA, United States
i Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
j Division of Molecular Pathology, Institute of Medical Sciences, University of TokyoTokyo, Japan
k Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, University of TokyoTokyo, Japan
l Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
m Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, United States
n Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of TokyoTokyo, Japan
o Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan
p Department of Internal Medicine, University of Turku, Turku, Finland
q Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Turku, Finland
r Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
s Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University HospitalOslo, Norway
t K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
u Department of Neurology, Oslo University HospitalOslo, Norway
v Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
w Department of Neurology and Cerebrovascular Disease Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
x Rajendra Institute of Medical Sciences, Ranchi, India
y Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
z Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
aa Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
ab Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
ac Neuroscience and Ageing Research Unit Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria
ad Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
ae Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands
af Edmond and Lily Safra Center for Brain Sciences, Hebrew University of JerusalemJerusalem, Israel
ag Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
ah Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
ai Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Health System, Danville, VA, United States
aj Department of Public Health Sciences, College of Medicine, Pennsylvania State University, State CollegePA, United States
ak Stroke Pharmacogenomics and Genetics Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
al Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
am Danish Twin Registry, Department of Public Health, University of Southern Denmark, Odense, Denmark
an Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
ao Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, United States
ap Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
aq Data Tecnica International, Glen Echo, MD, United States
ar Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
as Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States
at British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
au Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, United Kingdom
av Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, United States
aw Department of Surgery, University of Pennsylvania, Philadelphia, PA, United States
ax Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu UniversityFukuoka, Japan
ay University of Lille, INSERM U1167, RID-AGE, LabEx DISTALZ, Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
az Public Health Department, CHU Lille, Lille, France
ba Institut Pasteur de Lille, Lille, France
bb Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States
bc UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, University UtrechtUtrecht, Netherlands
bd Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
be Department of Biostatistics, University of Washington, Seattle, WA, United States
bf Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
bg Institute of Clinical Medicine, Faculty of Medicine, University of OsloOslo, Norway
bh Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University HospitalOslo, Norway
bi Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, United States
bj Harvard Medical School, Boston, MA, United States
bk MRC Population Health Research Unit, University of Oxford, Oxford, United Kingdom
bl Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
bm NeuroGenomics and Informatics Center, Washington University School of Medicine, Saint Louis, MO, USA
bn VA Maryland Health Care System, Baltimore, MD, United States
bo Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
bp Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA
bq GenomesForLife-GCAT Lab Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
br Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin BerlinBerlin, Germany
bs Center for Stroke Research BerlinBerlin, Germany
bt German Center for Neurodegenerative Diseases (DZNE), partner site BerlinBerlin, Germany
bu German Centre for Cardiovascular Research (DZHK), partner site BerlinBerlin, Germany
bv Post-Graduation Program on Health and Environment, Department of Medicine and Joinville Stroke Biobank, University of the Region of JoinvilleSanta Catarina, Brazil
bw Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht UniversityUtrecht, Netherlands
bx Icelandic Heart Association, Kopavogur, Iceland
by Faculty of Medicine, University of Iceland, Reykjavik, Iceland
bz Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu UniversityFukuoka, Japan
ca Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
cb Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
cc Institute for Molecular Medicine Finland, Helsinki, Finland
cd Clinical Trial Service and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
ce Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
cf Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
cg Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
ch Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom
ci British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
cj Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
ck Los Angeles County Department of Public Health, Los Angeles, CA, United States
cl Institute of Biomedicine, Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
cm Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
cn Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu UniversityFukuoka, Japan
co Department of Biology, Brody School of Medicine Center for Health Disparities, East Carolina University, Greenville, NC, United States
cp Department of Neurology and Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, United States
cq Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
cr Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, United States
cs Department of Neurology, Korea University Guro HospitalSeoul, South Korea
ct Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
cu Swiss Institute of Bioinformatics, Lausanne, Switzerland
cv University Center for Primary Care and Public Health, Lausanne, Switzerland
cw Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science CenterBeijing, China
cx Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
cy Institute of Human Genetics, Technical University of Munich, Munich, Germany
cz Institute of Human Genetics, German Research Center for Environmental Health, Helmholtz Zentrum MünchenNeuherberg, Germany
da Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
db Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, United States
dc Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
dd Department of Neurology, University Hospital Würzburg, Würzburg, Germany
de MIND Center, University of Mississippi Medical Center, Jackson, MS, United States
df Department of Clinical Biochemistry, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark
dg Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
dh College of Medicine Nursing and Health Science, NUI Galway, Galway, Ireland
di Department of Genome Informatics, Graduate School of Medicine, University of TokyoTokyo, Japan
dj Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
dk Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
dl Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
dm Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan
dn Weill Institute for Neurosciences, University of California, San Francisco, CA, United States
do Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum MünchenNeuherberg, Germany
dp Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilian University Munich, Munich, Germany
dq German Centre for Cardiovascular Research (DZHK), partner site Munich, Munich, Germany
dr Department of Epidemiology, University of Washington, Seattle, WA, United States
ds Department of Health Systems and Population Health, University of Washington, Seattle, WA, United States
dt McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, United States
du Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
dv Evelyn F. McKnight Brain Institute, Gainesville, FL, United States
dw Division of Cardiology, Department of Medicine, Columbia University, New York, NY, USA
dx Stroke Unit, Department of Neurology, Oslo University HospitalOslo, Norway
dy Research and Development, Norwegian Air Ambulance FoundationOslo, Norway
dz Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, United States
ea Framingham Heart Study, Framingham, MA, United States
eb Institute for Community Medicine, Greifswald, University Medicine Greifswald, Germany
ec Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States
ed Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA, United States
ee Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
ef Atlanta VA Health Care System, Decatur, GA, United States
eg Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States
eh Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Unviersity Hospital, Gothenburg, Sweden
ei Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands
ej Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
ek Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht UniversityUtrecht, Netherlands
el Department of Neurology and Neurosurgery, University of TartuTartu, Estonia
em Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
en Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
eo Department of Medicine, Division of Cardiovascular Disease, Emory University School of Medicine, Atlanta, GA, United States
ep Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
eq Division of Genome Science, Department of Precision Medicine, Cheongju, National Institute of Health, South Korea
er Research Unit Molecular Epidemiology, Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum MünchenNeuherberg, Germany
es Department of Psychiatry and Psychotherapy, Greifswald, University Medicine Greifswald, Germany
et German Center for Neurodegenerative Diseases (DZNE), site Rostock/Greifswald, Rostock, Germany
eu Netherlands Heart InstituteUtrecht, Netherlands
ev Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, Netherlands
ew Department of Clinical Genetics, Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands
ex Latin American Brain Health (BrainLat), Universidad Adolfo IbáñezSantiago, Chile
ey Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA
ez Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
fa Department of Neurology, University of Virginia, Charlottesville, VA, United States
fb Department of Public Health Science, University of Virginia, Charlottesville, VA, United States
fc McGill Genome Centre, Montreal, QC, Canada
fd Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States
fe Geisinger Neuroscience Institute, Geisinger Health System, Danville, PA, United States
ff Department of Neurology, College of Medicine, Pennsylvania State University, State CollegePA, United States
fg Klinik für Neurologie, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
fh Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany
fi Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany
fj Department of Neurology, University of Washington, Seattle, WA, United States
fk Institute for Health Promotion, Graduate School of Public Health, Yonsei UniversitySeoul, South Korea
fl Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
fm Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
fn Department of Surgery and Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States
fo Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, United States
fp Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
fq Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
fr Division of Medicine, Turku University Hospital, Turku, Finland
fs Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
ft Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States
fu Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan
fv Department of Neurology, Boston University School of Medicine, Boston, MA, United States
fw Department of Medicine, University of Ibadan, Ibadan, Nigeria
fx Munich Cluster for Systems Neurology, Munich, Germany
fy German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
fz Department of Neurology, Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France

Abstract
Previous genome-wide association studies (GWASs) of stroke – the second leading cause of death worldwide – were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries. © 2022. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Increased white matter glycolysis in humans with cerebral small vessel disease” (2022) Nature Aging

Increased white matter glycolysis in humans with cerebral small vessel disease
(2022) Nature Aging, 2 (11), pp. 991-999. 

Brier, M.R.a , Blazey, T.b , Raichle, M.E.b , Morris, J.C.a , Benzinger, T.L.S.b , Vlassenko, A.G.b , Snyder, A.Z.a b b , Goyal, M.S.a b b

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

Abstract
White matter lesions in cerebral small vessel disease are related to ischemic injury and increase the risk of stroke and cognitive decline. Pathological changes due to cerebral small vessel disease are increasingly recognized outside of discrete lesions, but the metabolic alterations in nonlesional tissue has not been described. Aerobic glycolysis is critical to white matter myelin homeostasis and repair. In this study, we examined cerebral metabolism of glucose and oxygen as well as blood flow in individuals with and without cerebral small vessel disease using multitracer positron emission tomography. We show that glycolysis is relatively elevated in nonlesional white matter in individuals with small vessel disease relative to healthy, age-matched controls. On the other hand, in young healthy individuals, glycolysis is relatively low in areas of white matter susceptible to lesion formation. These results suggest that increased white matter glycolysis is a marker of pathology associated with small vessel disease. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAKL2TR002346, P01AG003991, P01AG026276, P50AG005681, R01AG053503, R01AG057536, R25NS090978, RF1AG073210
Massachusetts General HospitalMGH
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGAD
Siemens Healthineers

Document Type: Article
Publication Stage: Final
Source: Scopus

CROI 2022: neurologic complications of HIV-1, SARS-CoV-2, and other pathogens” (2022) Topics in Antiviral Medicine

CROI 2022: neurologic complications of HIV-1, SARS-CoV-2, and other pathogens
(2022) Topics in Antiviral Medicine, 30 (4), pp. 475-489. 

Anderson, A.M.a , Letendre, S.L.b , Ances, B.M.c

a Emory University, Atlanta, GA, United States
b University of Califoria San Diego, San Diego, CA, United States
c Washington University at St Louis, St Louis, MO, United States

Abstract
The 2022 Conference on Retroviruses and Opportunistic Infections featured new and important findings about the neurologic complications of HIV-1, COVID-19, and other infections. Long-term analyses identified that cognitive decline over time, phenotypic aging, and stroke are associated with various comorbidities in people with HIV. Neuroimaging studies showed greater neuroinflammation, white matter damage, demyelination, and overall brain aging in people with chronic HIV infection. Childhood trauma and exposure to environmental pollutants contribute to these neuroimaging findings. Studies of blood and cerebrospinal fluid biomarkers showed that systemic inflammation, neurodegeneration, endothelial activation, oxidative stress, and iron dysregulation are associated with worse cognition in people with HIV. Some animal studies focused on myeloid cells of the central nervous system, but other animal and human studies showed that lymphoid cells also contribute to HIV neuropathogenesis. The deleterious central nervous system effects of polypharmacy and anticholinergic drugs in people with HIV were demonstrated. In contrast, a large randomized controlled trial showed that integrase strand transfer inhibitor therapy was not associated with neurotoxicity. Studies of cryptococcal meningitis demonstrated he cost-effectiveness of single high-dose liposomal amphotericin and the prognostic value of the cryptococcal antigen lateral flow assay. People hospitalized with COVID-19 had more anxiety over time after discharge. The SARS-CoV-2 nucleocapsid antigen is present in cerebrospinal fluid in the absence of viral RNA. Systemic inflammation, astrocyte activation, and tryptophan metabolism pathways are associated with post-COVID-19 neurologic syndromes. Whether these processes are independent or intertwined during HIV-1 and COVID-19 infections requires further study.

Document Type: Article
Publication Stage: Final
Source: Scopus

Identification of a Stress-Sensitive Anorexigenic Neurocircuit From Medial Prefrontal Cortex to Lateral Hypothalamus” (2022) Biological Psychiatry

Identification of a Stress-Sensitive Anorexigenic Neurocircuit From Medial Prefrontal Cortex to Lateral Hypothalamus
(2022) Biological Psychiatry, . 

Clarke, R.E.a , Voigt, K.b , Reichenbach, A.a , Stark, R.a , Bharania, U.a , Dempsey, H.a , Lockie, S.H.a , Mequinion, M.a , Lemus, M.a , Wei, B.a , Reed, F.a , Rawlinson, S.a , Nunez-Iglesias, J.c , Foldi, C.J.a , Kravitz, A.V.d , Verdejo-Garcia, A.b , Andrews, Z.B.a

a Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, VIC, Australia
b Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia
c Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
d Departments of Psychiatry, Anesthesiology, and Neuroscience, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: A greater understanding of how the brain controls appetite is fundamental to developing new approaches for treating diseases characterized by dysfunctional feeding behavior, such as obesity and anorexia nervosa. Methods: By modeling neural network dynamics related to homeostatic state and body mass index, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans (n = 53). We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice. Results: In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under nonstressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose seeking in mice. Conclusions: These studies identify a glutamatergic mPFC-LH circuit as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake. © 2022 Society of Biological Psychiatry

Author Keywords
Calcium imaging;  Chemogenetics;  FED3;  Feeding behavior;  Network modeling;  Optogenetics

Funding details
National Health and Medical Research CouncilNHMRCAPP1126724, APP1154974, APP2013243

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