Scopus list of publications for July 30, 2023
Dorsal striatal response to taste is modified by obesity and insulin resistance
(2023) Obesity, 31 (8), pp. 2065-2075.
Dunn, J.P.a b , Lamichhane, B.c , Smith, G.I.b , Garner, A.a , Wallendorf, M.d , Hershey, T.e , Klein, S.b
a VA St. Louis Health Care System, St. Louis, MO, United States
b Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Departments of Psychiatry and Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Objective: In preclinical models, insulin resistance in the dorsal striatum (DS) contributes to overeating. Although human studies support the concept of central insulin resistance, they have not investigated its effect on consummatory reward-induced brain activity. Methods: Taste-induced activation was assessed in the caudate and putamen of the DS with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Three phenotypically distinct groups were studied: metabolically healthy lean, metabolically healthy obesity, and metabolically unhealthy obesity (MUO; presumed to have central insulin resistance). Participants with MUO also completed a weight loss intervention followed by a second functional magnetic resonance imaging session. Results: The three groups were significantly different at baseline consistent with the design. The metabolically healthy lean group had a primarily positive BOLD response, the MUO group had a primarily negative BOLD response, and the metabolically healthy obesity group had a response in between the two other groups. Food craving was predicted by taste-induced activation. After weight loss in the MUO group, taste-induced activation increased in the DS. Conclusions: These data support the hypothesis that insulin resistance and obesity contribute to aberrant responses to taste in the DS, which is only partially attenuated by weight loss. Aberrant responses to food exposure may be a barrier to weight loss. © 2023 The Obesity Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Funding details
National Institutes of HealthNIHDK20579, DK56341, UL1 TR000445, UL1TR002345
U.S. Department of Veterans AffairsVA1IK2CX000943
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish HospitalFBJH
Centene CorporationP19‐00559
Document Type: Article
Publication Stage: Final
Source: Scopus
Kappa opioid receptor activation increases thermogenic energy expenditure which drives increased feeding
(2023) iScience, 26 (7), art. no. 107241, .
Cone, A.L.a , Wu, K.K.a , Kravitz, A.V.a b c , Norris, A.J.a
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Opioid receptors, including the kappa opioid receptor (KOR), exert control over thermoregulation and feeding behavior. Notably, activation of KOR stimulates food intake, leading to postulation that KOR signaling plays a central role in managing energy intake. KOR has also been proposed as a target for treating obesity. Herein, we report studies examining how roles for KOR signaling in regulating thermogenesis, feeding, and energy balance may be interrelated using pharmacological interventions, genetic tools, quantitative thermal imaging, and metabolic profiling. Our findings demonstrate that activation of KOR in the central nervous system causes increased energy expenditure via brown adipose tissue activation. Importantly, pharmacologic, or genetic inhibition of brown adipose tissue thermogenesis prevented the elevated food intake triggered by KOR activation. Furthermore, our data reveal that KOR-mediated thermogenesis elevation is reversibly disrupted by chronic high-fat diet, implicating KOR signaling as a potential mediator in high-fat diet-induced weight gain. © 2023 The Author(s)
Author Keywords
Cell biology; Endocrinology; Neuroscience
Funding details
National Institutes of HealthNIH5K08MH119538, P30 DK020579
Document Type: Article
Publication Stage: Final
Source: Scopus
Analysis of brain edema in RHAPSODY
(2023) International Journal of Stroke, .
Schleicher, R.L.a , Vorasayan, P.a b , McCabe, M.E.c , Bevers, M.B.d , Davis, T.P.e , Griffin, J.H.f , Hinduja, A.g , Jadhav, A.P.h , Lee, J.-M.i , Sawyer, R.N., Jrj , Zlokovic, B.V.k , Sheth, K.N.l , Fedler, J.K.c , Lyden, P.k m , Kimberly, W.T.a , on behalf of the NN104 Investigatorsn
a Division of Neurocritical Care and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
b Division of Neurology, Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
c Department of Biostatistics, University of Iowa, Iowa City, IA, United States
d Divisions of Stroke, Cerebrovascular and Critical Care Neurology, Brigham and Women’s Hospital, Boston, MA, United States
e Department of Pharmacology, University of Arizona Health Sciences, Tucson, AZ, United States
f Department of Molecular Medicine, Scripps Research, La JollaCA, United States
g Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, United States
h Barrow Neurological Institute, Phoenix, AZ, United States
i Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
j Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
k Department of Physiology and Neuroscience, Keck School of Medicine of USC, Los Angeles, CA, United States
l Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, United States
m Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA, United States
Abstract
Background: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema. Aims: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers. Methods: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment. Results: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = –0.57, p = 0.0001) and HVR (ρ = –0.66, p < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR (p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm. Conclusions: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process. © 2023 World Stroke Organization.
Author Keywords
edema; imaging markers; Ischemic stroke
Funding details
Biogen
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Functional trajectories during innate spinal cord repair
(2023) Frontiers in Molecular Neuroscience, 16, art. no. 1155754, .
Jensen, N.O.a b , Burris, B.a b , Zhou, L.a b , Yamada, H.a b , Reyes, C.a b , Pincus, Z.a c , Mokalled, M.H.a b
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Adult zebrafish are capable of anatomical and functional recovery following severe spinal cord injury. Axon growth, glial bridging and adult neurogenesis are hallmarks of cellular regeneration during spinal cord repair. However, the correlation between these cellular regenerative processes and functional recovery remains to be elucidated. Whereas the majority of established functional regeneration metrics measure swim capacity, we hypothesize that gait quality is more directly related to neurological health. Here, we performed a longitudinal swim tracking study for 60 individual zebrafish spanning 8 weeks of spinal cord regeneration. Multiple swim parameters as well as axonal and glial bridging were integrated. We established rostral compensation as a new gait quality metric that highly correlates with functional recovery. Tensor component analysis of longitudinal data supports a correspondence between functional recovery trajectories and neurological outcomes. Moreover, our studies predicted and validated that a subset of functional regeneration parameters measured 1 to 2 weeks post-injury is sufficient to predict the regenerative outcomes of individual animals at 8 weeks post-injury. Our findings established new functional regeneration parameters and generated a comprehensive correlative database between various functional and cellular regeneration outputs. Copyright © 2023 Jensen, Burris, Zhou, Yamada, Reyes, Pincus and Mokalled.
Author Keywords
functional recovery; spinal cord injury; spinal cord regeneration; swim assay; zebrafish
Funding details
National Institutes of HealthNIHR01 NS113915, R01 NS123708
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
Precipitating Mechanisms of Falls in Preclinical Alzheimer’s Disease
(2023) Journal of Alzheimer’s Disease Reports, 7 (1), pp. 739-750.
Keleman, A.A.a , Nicosia, J.b , Bollinger, R.M.a , Wisch, J.K.b , Hassenstab, J.b c , Morris, J.C.b e , Ances, B.M.b d e , Balota, D.A.c , Stark, S.L.a b
a Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Individuals with Alzheimer’s disease (AD) are more than twice as likely to incur a serious fall as the general population of older adults. Although AD is commonly associated with cognitive changes, impairments in other clinical measures such as strength or functional mobility (i.e., gait and balance) may precede symptomatic cognitive impairment in preclinical AD and lead to increased fall risk. Objective: To examine mechanisms (i.e., functional mobility, cognition, AD biomarkers) associated with increased falls in cognitively normal older adults. Methods: This 1-year study was part of an ongoing longitudinal cohort study. We examined the relationships among falls, clinical measures of functional mobility and cognition, and neuroimaging AD biomarkers in cognitively normal older adults. We also investigated which domain(s) best predicted fall propensity and severity through multiple regression models. Results: A total of 182 older adults were included (mean age 75 years, 53% female). A total of 227 falls were reported over the year; falls per person ranged from 0-16 with a median of 1. Measures of functional mobility were the best predictors of fall propensity and severity. Cognition and AD biomarkers were associated with each other but not with the fall outcome measures. Conclusion: These results suggest that, although subtle changes in cognition may be more closely associated with AD neuropathology, functional mobility indicators better predict falls in cognitively normal older adults. This study adds to our understanding of the mechanisms underlying falls in older adults and could lead to the development of targeted fall prevention strategies. © 2023 – The authors. Published by IOS Press.
Author Keywords
Alzheimer’s disease; cognition; falls; functional mobility
Funding details
National Institutes of HealthNIH5TL1TR002344-05, P01AG026276, P01AG03991, P30AG066444, R01AG057680, UL1 TR002345
Document Type: Article
Publication Stage: Final
Source: Scopus
Locus specific endogenous retroviral expression associated with Alzheimer’s disease
(2023) Frontiers in Aging Neuroscience, 15, art. no. 1186470, .
Dawson, T.a b , Rentia, U.a , Sanford, J.c , Cruchaga, C.c , Kauwe, J.S.K.d , Crandall, K.A.a b
a Computational Biology Institute, The George Washington University, Washington, DC, United States
b Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biology, Brigham Young University, Provo, UT, United States
Abstract
Introduction: Human endogenous retroviruses (HERVs) are transcriptionally-active remnants of ancient retroviral infections that may play a role in Alzheimer’s disease. Methods: We combined two, publicly available RNA-Seq datasets with a third, novel dataset for a total cohort of 103 patients with Alzheimer’s disease and 45 healthy controls. We use telescope to perform HERV quantification for these samples and simultaneously perform gene expression analysis. Results: We identify differentially expressed genes and differentially expressed HERVs in Alzheimer’s disease patients. Differentially expressed HERVs are scattered throughout the genome; many of them are members of the HERV-K superfamily. A number of HERVs are correlated with the expression of dysregulated genes in Alzheimer’s and are physically proximal to genes which drive disease pathways. Discussion: Dysregulated expression of ancient retroviral insertions in the human genome are present in Alzheimer’s disease and show localization patterns that may explain how these elements drive pathogenic gene expression. Copyright © 2023 Dawson, Rentia, Sanford, Cruchaga, Kauwe and Crandall.
Author Keywords
Alzheimer’s disease; endogenous retrovirus; gene expression; HERV; RNA-Seq
Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P01AG0399, P30AG06644, R01AG044546, R01AG078964, RF1AG053303, RF1AG058501, RF1AG071706, U01AG058922
U.S. Department of DefenseDODLI- W81XWH2010849
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAZEN-22-848604
Brigham Young UniversityBYU
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZI
Document Type: Article
Publication Stage: Final
Source: Scopus
SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity. Nat Immunol. 2023 Jul;24(7):1188-1199.
Fixsen BR, Han CZ, Zhou Y, Spann NJ, Saisan P, Shen Z, Balak C, Sakai M, Cobo I, Holtman IR, Warden AS, Ramirez G, Collier JG, Pasillas MP, Yu M, Hu R, Li B, Belhocine S, Gosselin D, Coufal NG, Ren B, Glass CK.
Abstract
Spalt-like transcription factor 1 (SALL1) is a critical regulator of organogenesis and microglia identity. Here we demonstrate that disruption of a conserved microglia-specific super-enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knockout mice, we provide evidence for functional interactions between SALL1 and SMAD4 required for microglia-specific gene expression. SMAD4 binds directly to the Sall1 super-enhancer and is required for Sall1 expression, consistent with an evolutionarily conserved requirement of the TGFβ and SMAD homologs Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Unexpectedly, SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in enhancer knockout microglia, thereby enforcing microglia-specific functions of the TGFβ–SMAD signaling axis. © 2023, The Author(s).
Funding
We thank the UCSD Transgenic Core for assistance with creating the EKO mouse line used for this study. We thank C. Fine, V. Nguyen and J. Olvera for assistance with sorting. We thank L. Van Ael for assistance with manuscript preparation. We thank J. Schlachetzki for experimental advice. This publication includes data generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). These studies were supported by NIH grant NS096170 (C.K.G. and N.G.C.), CAF grant 306938 (C.K.G.), JPB Foundation grant KR29574 (C.K.G.), NIH Grant 1F30AG062159 (B.R.F.), NIH Grant K99MH129983 (C.Z.H.), NIH Grant NS109200 (N.G.C.) and R01 NS124637 (N.G.C.).