Hope Center member publications

Epigenetic regulation in Huntington’s disease
(2021) Neurochemistry International, 148, art. no. 105074, .

Hyeon, J.W.^a , Kim, A.H.^{a b c d e} , Yano, H.^a b c e 

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Huntington’s disease (HD) is a devastating and fatal monogenic neurodegenerative disorder characterized by progressive loss of selective neurons in the brain and is caused by an abnormal expansion of CAG trinucleotide repeats in a coding exon of the huntingtin (HTT) gene. Progressive gene expression changes that begin at premanifest stages are a prominent feature of HD and are thought to contribute to disease progression. Increasing evidence suggests the critical involvement of epigenetic mechanisms in abnormal transcription in HD. Genome-wide alterations of a number of epigenetic modifications, including DNA methylation and multiple histone modifications, are associated with HD, suggesting that mutant HTT causes complex epigenetic abnormalities and chromatin structural changes, which may represent an underlying pathogenic mechanism. The causal relationship of specific epigenetic changes to early transcriptional alterations and to disease pathogenesis require further investigation. In this article, we review recent studies on epigenetic regulation in HD with a focus on DNA and histone modifications. We also discuss the contribution of epigenetic modifications to HD pathogenesis as well as potential mechanisms linking mutant HTT and epigenetic alterations. Finally, we discuss the therapeutic potential of epigenetic-based treatments. © 2021 Elsevier Ltd

Author Keywords
DNA methyltransferases (DNMTs);  Epigenetic regulation;  Epigenetic-based therapy;  Huntington’s disease (HD);  Neurodegeneration;  Transcription

Funding details
National Institutes of HealthNIHR01 NS051255, R01 NS111014, R21 NS103509

Document Type: Article
Publication Stage: Final
Source: Scopus

Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala
(2021) eLife, 10, . 

Samineni, V.K.^a , Grajales-Reyes, J.G.^a b c , Grajales-Reyes, G.E.^d , Tycksen, E.^e , Copits, B.A.^a , Pedersen, C.^f , Ankudey, E.S.^a , Sackey, J.N.^a , Sewell, S.B.^a , Bruchas, M.R.^a g h , Gereau, R.W.^a f h

^a Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, United States
^c Neuroscience Program, Washington University School of Medicine, St. Louis, United States
^d Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, United States
^e Genome Technology Access Center, Washington University School of Medicine, Seattle, United States
^f Department of Biomedical Engineering, University of Washington, Seattle, United States
^g Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, United States
^h Departmentsof Neuroscience and Biomedical Engineering, Washington University School of Medicine, United States

Abstract
Itch is an unpleasant sensation that elicits robust scratching and aversive experience. However, the identity of the cells and neural circuits that organize this information remains elusive. Here, we show the necessity and sufficiency of chloroquine-activated neurons in the central amygdala (CeA) for both itch sensation and associated aversion. Further, we show that chloroquine-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of chloroquine-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral tracing experiments demonstrate that these neurons send projections to the ventral periaqueductal gray that are critical in modulation of itch. These findings reveal a cellular and circuit signature of CeA neurons orchestrating behavioral and affective responses to pruritus in mice. © 2021, Samineni et al.

Author Keywords
affect;  anxiety;  central amygdala;  itch;  mouse;  neuroscience;  pain;  RNAseq

Document Type: Article
Publication Stage: Final
Source: Scopus

Label-Free Macroscopic Fluorescence Lifetime Imaging of Brain Tumors
(2021) Frontiers in Oncology, 11, art. no. 666059, . 

Lukina, M.^a , Yashin, K.^a , Kiseleva, E.E.^a , Alekseeva, A.^b , Dudenkova, V.^a , Zagaynova, E.V.^a c , Bederina, E.^a , Medyanic, I.^a , Becker, W.^d , Mishra, D.^e , Berezin, M.^e , Shcheslavskiy, V.I.^a d , Shirmanova, M.^a

^a Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation
^b Department of Neuromorphology, Research Institute of Human Morphology, Moscow, Russian Federation
^c Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russian Federation
^d BeckerHickl GmbH, Berlin, Germany
^e Department of Radiology, Washington University School of Medicine, St LouisMO, United States

Abstract
Advanced stage glioma is the most aggressive form of malignant brain tumors with a short survival time. Real-time pathology assisted, or image guided surgical procedures that eliminate tumors promise to improve the clinical outcome and prolong the lives of patients. Our work is focused on the development of a rapid and sensitive assay for intraoperative diagnostics of glioma and identification of optical markers essential for differentiation between tumors and healthy brain tissues. We utilized fluorescence lifetime imaging (FLIM) of endogenous fluorophores related to metabolism of the glioma from freshly excised brains tissues. Macroscopic time-resolved fluorescence images of three intracranial animal glioma models and surgical samples of patients’ glioblastoma together with the white matter have been collected. Several established and new algorithms were applied to identify the imaging markers of the tumors. We found that fluorescence lifetime parameters characteristic of the glioma provided background for differentiation between the tumors and intact brain tissues. All three rat tumor models demonstrated substantial differences between the malignant and normal tissue. Similarly, tumors from patients demonstrated statistically significant differences from the peritumoral white matter without infiltration. While the data and the analysis presented in this paper are preliminary and further investigation with a larger number of samples is required, the proposed approach based on the macroscopic FLIM has a high potential for diagnostics of glioma and evaluation of the surgical margins of gliomas. © Copyright © 2021 Lukina, Yashin, Kiseleva, Alekseeva, Dudenkova, Zagaynova, Bederina, Medyanic, Becker, Mishra, Berezin, Shcheslavskiy and Shirmanova.

Author Keywords
autofluorescence;  FLIM;  fluorescence lifetime imaging;  glioblastoma;  image processing;  rat glioma model

Document Type: Article
Publication Stage: Final
Source: Scopus

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer’s disease
(2021) eLife, 10, . 

Pichet Binette, A.^a b , Theaud, G.^c , Rheault, F.^d , Roy, M.^c , Collins, D.L.^e , Levin, J.^f g , Mori, H.^h , Lee, J.H.ⁱ , Farlow, M.R.^j , Schofield, P.^k l , Chhatwal, J.P.^m , Masters, C.L.ⁿ , Benzinger, T.^o p , Morris, J.^o p , Bateman, R.^o p , Breitner, J.C.^a b , Poirier, J.^a b , Gonneaud, J.^b q , Descoteaux, M.^c , Villeneuve, S.^a b e , DIAN Study Group^r , PREVENT-AD Research Group^s

^a Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Canada
^b Douglas Mental Health University Institute, Montreal, Canada
^c Sherbrooke Connectivity Imaging Laboratory (SCIL), Université de Sherbrooke, Sherbrooke, Canada
^d Electrical Engineering, Vanderbilt University, Nashville, United States
^e McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Canada
^f Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^g German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^h Department of Clinical Neuroscience, Osaka City University Medical SchoolOsaka, Japan
ⁱ Department of Neurology, Asan Medical Center, University of Ulsan College of MedicineSeoul, South Korea
^j Department of Neurology, Indiana University, Bloomington, United States
^k Neuroscience Research Australia, Sydney, Australia
^l School of Medical Sciences, UNSW Sydney, Sydney, Australia
^m Harvard Medical School, Massachusetts General Hospital, Boston, United States
ⁿ University of Melbourne, The Florey Institute of Neuroscience and Mental Health, Parkville, Australia
^o Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, United States
^p Department of Neurology, Washington University School of Medicine, St. Louis, United States
^q Normandie Univ, UNICAEN, INSERM, Institut Blood and Brain @ Caen-Normandie, Caen, France

Abstract
Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer’s disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau burden in both cohorts. Associations were found in the posterior cingulum and uncinate fasciculus in preclinical sporadic AD, and in the anterior and posterior cingulum in presymptomatic mutation carriers. These results suggest that microstructural alterations accompany pathological accumulation as early as the preclinical stage of both sporadic and autosomal dominant AD. © 2021, Pichet Binette et al.

Author Keywords
cingulum;  diffusion MRI;  free-water;  human;  neuroscience;  PET;  uncinate fasciculus

Document Type: Article
Publication Stage: Final
Source: Scopus

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration
(2021) Journal of Lipid Research, 62, art. no. 100079, . 

Spears, L.D.^a , Adak, S.^a , Dong, G.^a b , Wei, X.^a , Spyropoulos, G.^c , Zhang, Q.^a , Yin, L.^a , Feng, C.^a , Hu, D.^a , Lodhi, I.J.^a , Hsu, F.-F.^a , Rajagopal, R.^d , Noguchi, K.K.^e , Halabi, C.M.^c , Brier, L.^f , Bice, A.R.^f , Lananna, B.V.^g , Musiek, E.S.^g , Avraham, O.^h , Cavalli, V.^h , Holth, J.K.^g , Holtzman, D.M.^g , Wozniak, D.F.^e , Culver, J.P.^f , Semenkovich, C.F.^a i

^a Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University, St. Louis, MO, United States
^b Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
^c Department of Pediatrics, Washington University, St. Louis, MO, United States
^d Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States
^e Department of Psychiatry, Washington University, St. Louis, MO, United States
^f Department of Radiology, Washington University, St. Louis, MO, United States
^g Department of Neurology, Washington University, St. Louis, MO, United States
^h Department of Neuroscience, Washington University, St. Louis, MO, United States
ⁱ Department of Cell Biology and Physiology, Washington University, St. Louis, MO, United States

Abstract
Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice. © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funding details
National Institutes of HealthNIHDK20579, NS074969, DK101392, K08HL135400, AG061776, GM103422, DK56341
National Center for Advancing Translational SciencesNCATSUL1 TR000448, U54 HD087011
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Hope Center for Neurological Disorders
American Heart AssociationAHA
China Scholarship CouncilCSC201608420067

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluation of SAMP8 Mice as a Model for Sleep-Wake and Rhythm Disturbances Associated with Alzheimer’s Disease: Impact of Treatment with the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant
(2021) Journal of Alzheimer’s Disease, 81 (3), pp. 1151-1167.

Beuckmann, C.T.^a , Suzuki, H.^a , Musiek, E.S.^b , Ueno, T.^a , Sato, T.^a , Bando, M.^a , Osada, Y.^a , Moline, M.^c 

^a Eisai Co. Ltd., Tsukuba, Ibaraki, Japan
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Eisai Inc., Woodcliff Lake, NJ, United States

Abstract
Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. © 2021-The authors. Published by IOS Press.

Author Keywords
Alzheimer’s disease;  animal models;  dual orexin receptor antagonist;  E2006;  in vivo;  irregular sleep-wake rhythm disorder;  lemborexant;  mouse;  orexin;  running wheel;  sleep

Document Type: Article
Publication Stage: Final
Source: Scopus

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model
(2021) Genes, Brain and Behavior, . 

Nygaard, K.R.^a b , Swift, R.G.^a b , Glick, R.M.^a b , Wagner, R.E.^b , Maloney, S.E.^b c , Gould, G.G.^d , Dougherty, J.D.^a b c

^a Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Intellectual and Developmental Disabilities Research Center, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Cellular and Integrative Physiology, University of Texas Health San Antonio, San Antonio, TX, United States

Abstract
Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A “Complete Deletion” (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus. © 2021 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Author Keywords
associative fear;  autoradiography;  behavioral genetics;  conditioned fear;  mouse model;  OXTR;  oxytocin;  oxytocin receptor antagonist;  SERT;  Williams Syndrome

Funding details
National Science FoundationNSFDGE‐1745038
National Institute of Mental HealthNIMH5R01MH107515‐05
National Institute of Child Health and Human DevelopmentNICHD
San Antonio Area FoundationSAAFD
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD103525

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

Functional Connectivity of Vermis Correlates with Future Gait Impairments in Parkinson’s Disease
(2021) Movement Disorders, . 

Maiti, B.^a , Rawson, K.S.^b , Tanenbaum, A.B.^a , Koller, J.M.^c , Snyder, A.Z.^a d , Campbell, M.C.^a d , Earhart, G.M.^a b e , Perlmutter, J.S.^{a b d e f}

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^f Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Dysfunction of cerebellar vermis contributes to gait abnormalities in multiple conditions and may play a key role in gait impairment in Parkinson’s disease (PD). Objective: The purpose of this study was to investigate whether altered resting-state functional connectivity of the vermis relates to subsequent impairment of specific domains of gait in PD. Methods: We conducted morphometric and resting-state functional connectivity MRI analyses contrasting 45 PD and 32 age-matched healthy participants. Quantitative gait measures were acquired with a GAITRite walkway at varying intervals after functional connectivity data acquisition. Results: At baseline, PD participants had significantly altered functional connectivity between vermis and sensorimotor cortex compared with controls. Altered vermal functional connectivity with bilateral paracentral lobules correlated with subsequent measures of variability in stride length, step time, and single support time after controlling for confounding variables including the interval between imaging and gait measures. Similarly, altered functional connectivity between vermis and left sensorimotor cortex correlated with mean stride length and its variability. Vermis volume did not relate to any gait measure. PD participants did not differ from controls in vermis volume or cortical thickness at the site of significant regional clusters. Only altered lobule V:sensorimotor cortex functional connectivity correlated with subsequent gait measures in exploratory analyses involving all the other cerebellar lobules. Conclusions: These results demonstrate that abnormal vermal functional connectivity with sensorimotor cortex, in the absence of relevant vermal or cortical atrophy, correlates with subsequent gait impairment in PD. Our data reflect the potential of vermal functional connectivity as a novel imaging biomarker of gait impairment in PD. © 2021 International Parkinson and Movement Disorder Society. © 2021 International Parkinson and Movement Disorder Society

Author Keywords
cerebellum;  functional connectivity;  gait impairment;  Parkinson disease;  vermis

Funding details
AT010753, HD092444, NS075321, NS103957, NS107281, NS110456
National Institutes of HealthNIHKL2 TR002346, NS065701, NS097799, NS116025, P30 NS098577‐01, RO1 NS075321‐02, RO1 NS097437
U.S. Department of DefenseDODDOD W81XWH‐217‐1‐0393
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDSTR 001456
National Endowment for the ArtsNEA1880026‐31‐21, AG050263, AG‐64937, ES029524, NS075527, NS092865, NS109487, R61 AT010753, U10NS077384, U19 NS110456, U54NS116025
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Huntington’s Disease Society of AmericaHDSA
Dystonia Medical Research FoundationDMRF1U01DA05103801, 2R01MH0967730A1, 5R01DK06483215, 5R01HD07085508, 5R01MH10403004, 5U01DA04112005, AG063974, AT010753‐01, AT010753‐02S1, NS075321‐02, NS097437, R01 NS097437, R01 NS10728101
American Brain FoundationABF
American Academy of NeurologyAAN
Stanford UniversitySU
CHDI FoundationCHDI
National Center for Advancing Translational SciencesNCATS
American Parkinson Disease AssociationAPDA
University of Pennsylvania
Foundation for Barnes-Jewish Hospital
ParkinsonfondenR01 HD092444, R61 AT114533, R61 AT114533‐S1, U01 NS113851
St. Louis American Parkinson Disease Association
McDonnell Center for Systems Neuroscience
Parkinson Study GroupPSG

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