Scopus list of publications for February 4, 2024
Dorsal hippocampus to nucleus accumbens projections drive reinforcement via activation of accumbal dynorphin neurons
(2024) Nature Communications, 15 (1), art. no. 750, .
Ibrahim, K.M.a b , Massaly, N.a b c , Yoon, H.-J.a b , Sandoval, R.a b , Widman, A.J.a b , Heuermann, R.J.a b d , Williams, S.a b , Post, W.a b , Pathiranage, S.a b , Lintz, T.a b , Zec, A.a b , Park, A.a b , Yu, W.e f , Kash, T.L.e f , Gereau, R.W., IVa b g , Morón, J.A.a b g h
a Department of Anesthesiology, Washington University Pain Center, St. Louis, MO 63110, United States
b Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
c Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, CA 90095, United States
d Department of Neurology, Washington University Pain Center, St. Louis, MO 63110, United States
e Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, United States
f Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, United States
g Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
h Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity’s role in reward-seeking behaviors. © 2024, The Author(s).
Funding details
National Institutes of HealthNIHDA042499, DA045463, DA054900, DA055047
Brain and Behavior Research FoundationBBRF
National Alliance for Research on Schizophrenia and DepressionNARSAD
Philippe Foundation
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma
(2024) Journal of Neuro-Oncology, .
Gonzalez-Aponte, M.F.a , Damato, A.R.a , Trebucq, L.L.b , Simon, T.a , Cárdenas-García, S.P.a , Cho, K.c d , Patti, G.J.c d , Golombek, D.A.b e , Chiesa, J.J.b , Rubin, J.B.f g , Herzog, E.D.a
a Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
b Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, Buenos Aires, Argentina
c Departments of Chemistry and Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO, United States
e Laboratorio Interdisciplinario del Tiempo (LITERA), Universidad de San Andrés, Buenos Aires, Victoria, B1644BID, Argentina
f Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
g Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
Abstract
Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. Methods and results: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. Conclusion: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy. Graphical abstract: [Figure not available: see fulltext.]. © 2024, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Chronotherapy; Circadian medicine; Circadian rhythms; DNA repair; GBM; TMZ
Funding details
National Institutes of HealthNIHF31CA250161, R25GM103757-10, T32NS121881-01
National Institute of Neurological Disorders and StrokeNINDSR21NS120003
University of WashingtonUW
Agencia Nacional de Promoción Científica y TecnológicaANPCyTPICT 1745-2017
Universidad Nacional de QuilmesUNQPUNQ 2285/22
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration
(2024) JCI Insight, 9 (2), art. no. e162771, .
Kanan, M.K.a , Sheehan, P.W.a , Haines, J.N.a , Gomez, P.G.a , Dhuler, A.a , Nadarajah, C.J.a , Wargel, Z.M.a , Freeberg, B.M.a , Nelvagal, H.R.b , Izumo, M.c , Takahashi, J.S.c d , Cooper, J.D.b , Davis, A.A.a , Musiek, E.S.a e
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Pediatrics, Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
d Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States
e Center On Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, MO, United States
Abstract
Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cellautonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after a-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD. © 2024, Kanan et al.
Funding details
National Institutes of HealthNIHK08NS101118, R01AG054517, T32AG058518
Howard Hughes Medical InstituteHHMI
National Cancer InstituteNCIP30 CA91842, UL1TR002345
Document Type: Article
Publication Stage: Final
Source: Scopus
Intraindividual variability in post-stroke cognition and its relationship with activities of daily living and social functioning: an ecological momentary assessment approach
(2024) Topics in Stroke Rehabilitation, .
Munsell, E.G.S.a b , Bui, Q.c , Kaufman, K.J.a , Tomazin, S.E.a , Regan, B.A.a , Lenze, E.J.d , Lee, J.-M.e , Mohr, D.C.f , Fong, M.W.M.g , Metts, C.L.h , Pham, V.d , Wong, A.W.K.a i
a Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL, United States
b Center for Education in Health Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Center for Behavioral Intervention Technologies, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
g Michigan Avenue Neuropsychologists, Chicago, IL, United States
h Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
i Department of Physical Medicine and Rehabilitation, Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Abstract
Introduction: Ecological momentary assessment (EMA) is a methodological approach to studying intraindividual variation over time. This study aimed to use EMA to determine the variability of cognition in individuals with chronic stroke, identify the latent classes of cognitive variability, and examine any differences in daily activities, social functioning, and neuropsychological performance between these latent classes. Methods: Participants (N = 202) with mild-to-moderate stroke and over 3-month post-stroke completed a study protocol, including smartphone-based EMA and two lab visits. Participants responded to five EMA surveys daily for 14 days to assess cognition. They completed patient-reported measures and neuropsychological assessments during lab visits. Using latent class analysis, we derived four indicators to quantify cognitive variability and identified latent classes among participants. We used ANOVA and Chi-square to test differences between these latent classes in daily activities, social functioning, and neuropsychological performance. Results: The latent class analysis converged on a three-class model. The moderate and high variability classes demonstrated significantly greater problems in daily activities and social functioning than the low class. They had significantly higher proportions of participants with problems in daily activities and social functioning than the low class. Neuropsychological performance was not statistically different between the three classes, although a trend approaching statistically significant difference was observed in working memory and executive function domains. Discussion: EMA could capture intraindividual cognitive variability in stroke survivors. It offers a new approach to understanding the impact and mechanism of post-stroke cognitive problems in daily life and identifying individuals benefiting from self-regulation interventions. © 2024 Taylor & Francis Group, LLC.
Author Keywords
cognition; cognitive rehabilitation; cognitive variability; ecological momentary assessment; mobile health; remote assessment; Stroke
Funding details
National Institutes of HealthNIH
American Occupational Therapy FoundationAOTF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD
(2024) Nature Medicine, .
Irwin, K.E.a b , Jasin, P.a , Braunstein, K.E.a , Sinha, I.R.a b , Garret, M.A.c , Bowden, K.D.a b , Chang, K.a d , Troncoso, J.C.a e , Moghekar, A.e , Oh, E.S.a f g , Raitcheva, D.h , Bartlett, D.h , Miller, T.i , Berry, J.D.c , Traynor, B.J.e j k l , Ling, J.P.a , Wong, P.C.a b
a Department of Pathology, Johns Hopkins Medicine, Baltimore, MD, United States
b Department of Neuroscience, Johns Hopkins Medicine, Baltimore, MD, United States
c Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA, United States
d Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
e Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
f Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, United States
g Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, MD, United States
h Biogen, Cambridge, MA, United States
i Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
j Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
k National Institute of Neurological Disorders, National Institutes of Health, Bethesda, MD, United States
l RNA Therapeutics Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, United States
Abstract
Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS–FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS–FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS–FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials. © 2024, The Author(s).
Funding details
National Science FoundationNSFOAC 1920103
National Institutes of HealthNIHR01NS095969, R33NS115161, UH3NS115608
U.S. Food and Drug AdministrationFDA1U01FD008129
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDS1ZIAAG000933
Alzheimer’s AssociationAA
ALS AssociationALSA
Richard and Susan Smith Family FoundationRSSFF
Robert Packard Center for ALS Research, Johns Hopkins University
Target ALS
Barnes Family Foundation
Karen Toffler Charitable TrustKTCT
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Patient Outcomes After Peripheral Nerve Injury Depend on Bimanual Dexterity and Preserved Use of the Affected Hand
(2024) Neurorehabilitation and Neural Repair, .
Kim, T.a , Lohse, K.R.b , Mackinnon, S.E.c , Philip, B.A.a
a Program in Occupational Therapy, 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 Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Little is known about how peripheral nerve injury affects human performance, behavior, and life. Hand use choices are important for rehabilitation after unilateral impairment, but rarely measured, and are not changed by the normal course of rehabilitation and daily life. Objective: To identify the relationship between hand use (L/R choices), motor performance, and patient-centered outcomes. Methods: Participants (n = 48) with unilateral peripheral nerve injury were assessed for hand use via Block Building Task, Motor Activity Log, and Edinburgh Handedness Inventory; dexterity (separately for each hand) via Nine-Hole Peg Test, Jebsen Taylor Hand Function Test, and a precision drawing task; patient-centered outcomes via surveys of disability, activity participation, and health-related quality of life; and injury-related factors including injury cause and affected nerve. Factor Analysis of Mixed Data was used to explore relationships between these variables. The data were analyzed under 2 approaches: comparing dominant hand (DH) versus non-dominant hand (NH), or affected versus unaffected hand. Results: The data were best explained by 5 dimensions. Good patient outcomes were associated with NH performance, DH performance (separately and secondarily to NH performance), and preserved function and use of the affected hand; whereas poor patient outcomes were associated with preserved but unused function of the affected hand. Conclusion: After unilateral peripheral nerve injury, hand function, hand usage, and patient life arise from a complex interaction of many factors. To optimize rehabilitation after unilateral impairment, new rehabilitation methods are needed to promote performance and use with the NH, as well as the injured hand. © The Author(s) 2024.
Author Keywords
hand dominance; lateralization; manual dexterity; peripheral nerve injury; quality of life
Funding details
National Institute of Neurological Disorders and StrokeNINDSR01 NS114046
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Peripheral Retinal Haemorrhages in a Patient with MOG-Associated Optic Neuritis
(2023) Neuro-Ophthalmology, .
Wilke, G.A.a , Spencer, M.b , Gilman, C.A.c , Guerriero, R.c , Bohm, P.d , Van Stavern, G.P.a , Lee, A.R.a
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Paediatrics, Washington University in St. Louis, St. Louis, MO, United States
c Division of Paediatric Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Neurology Consultants of Kansas, Wichita, KS, United States
Abstract
A 15-year-old female presented with headaches and bilateral vision loss. Fundoscopic examination revealed bilateral optic nerve oedema as well as peripheral retinal haemorrhages. Magnetic resonance imaging of the brain showed findings consistent with bilateral optic neuritis. The patient was started on high dose intravenous corticosteroids but her vision failed to improve. The presence of retinal haemorrhages raised concern that a vasculitis was underlying her symptoms, prompting an extensive work-up, which was unrevealing. Plasmapheresis was initiated and the patient’s vision eventually improved to 20/20 in both eyes. Ultimately, she was found to be positive for myelin oligodendrocyte glycoprotein (MOG) antibodies, consistent with a diagnosis of MOG-associated optic neuritis. The patient’s course was typical for MOG-associated optic neuritis but her peripheral retinal haemorrhages were atypical, which created diagnostic uncertainty. It is important to be aware of the possibility of retinal findings in this disease. We also review potential causes for retinal haemorrhages in optic neuritis. © 2023 Taylor & Francis Group, LLC.
Author Keywords
corticosteroids; MOG-associated optic neuritis; optic nerve oedema; plasma exchange; retinal haemorrhage
Document Type: Article
Publication Stage: Article in Press
Source: Scopus