Scopus list of publications for January 22, 2023
Passive functional mapping of receptive language cortex during general anesthesia using electrocorticography
(2023) Clinical Neurophysiology, 147, pp. 31-44.
Nourmohammadi, A.a b c , Swift, J.R.a b c , de Pesters, A.a c , Guay, C.S.d , Adamo, M.A.e , Dalfino, J.C.e , Ritaccio, A.L.f g , Schalk, G.a c h , Brunner, P.a b c f
a National Center for Adaptive Neurotechnologies, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Sciences, State University of New York at Albany, Albany, NY, United States
d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurosurgery, Albany Medical College, Albany, NY, United States
f Department of Neurology, Albany Medical College, Albany, NY, United States
g Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
h Chen Frontier Lab for Applied Neurotechnology, Tianqiao and Chrissy Chen Institute, Shanghai, China
Abstract
Objective: To investigate the feasibility of passive functional mapping in the receptive language cortex during general anesthesia using electrocorticographic (ECoG) signals. Methods: We used subdurally placed ECoG grids to record cortical responses to speech stimuli during awake and anesthesia conditions. We identified the cortical areas with significant responses to the stimuli using the spectro-temporal consistency of the brain signal in the broadband gamma (BBG) frequency band (70–170 Hz). Results: We found that ECoG BBG responses during general anesthesia effectively identify cortical regions associated with receptive language function. Our analyses demonstrated that the ability to identify receptive language cortex varies across different states and depths of anesthesia. We confirmed these results by comparing them to receptive language areas identified during the awake condition. Quantification of these results demonstrated an average sensitivity and specificity of passive language mapping during general anesthesia to be 49±7.7% and 100%, respectively. Conclusion: Our results demonstrate that mapping receptive language cortex in patients during general anesthesia is feasible. Significance: Our proposed protocol could greatly expand the population of patients that can benefit from passive language mapping techniques, and could eliminate the risks associated with electrocortical stimulation during an awake craniotomy. © 2022
Author Keywords
Awake craniotomy; Electrocorticography (ECoG); General anesthesia; Passive functional mapping; Receptive language cortex
Funding details
National Institutes of HealthNIHP41-EB018783, P50-MH109429, R01-EB026439, U01-NS108916, U01-NS128612, U24-NS109103
Army Research OfficeAROW911NF-14-1-0440
Document Type: Article
Publication Stage: Final
Source: Scopus
Striatal dopamine supports reward expectation and learning: A simultaneous PET/fMRI study
(2023) NeuroImage, 267, art. no. 119831, .
Calabro, F.J.a b , Montez, D.F.a d , Larsen, B.c , Laymon, C.M.b e , Foran, W.a , Hallquist, M.N.a f , Price, J.C.e g , Luna, B.a c
a Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychology, Washington University in St. Louis, MO, United States
e Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
f Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
g Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
Abstract
Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing underlying reward learning behaviors, based on the computation of reward prediction errors. However, competing evidence supports human dopamine signaling in the basal ganglia as also contributing to the generation of higher order learning heuristics. Here, we present data from a large (N = 81, 18–30yo), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with [11C]Raclopride (RAC), assessing striatal dopamine (DA) D2/3 receptor binding, during performance of a probabilistic reward learning task. Both fMRI activation and PET DA measures showed ventral striatum involvement for signaling rewards. However, greater DA release was uniquely associated with learning strategies (i.e., learning rates) that were more task-optimal within the best fitting reinforcement learning model. This DA response was associated with BOLD activation of a network of regions including anterior cingulate cortex, medial prefrontal cortex, thalamus and posterior parietal cortex, primarily during expectation, rather than prediction error, task epochs. Together, these data provide novel, human in vivo evidence that striatal dopaminergic signaling interacts with a network of cortical regions to generate task-optimal learning strategies, rather than representing reward outcomes in isolation. © 2022 The Authors
Author Keywords
Dopamine; PET/fMRI; Reinforcement learning
Funding details
National Institutes of HealthNIH2020, 2022, UL1TR001857
National Institute of Mental HealthNIMHMH080243
Indiana Clinical and Translational Sciences InstituteCTSI
Medical Center, University of PittsburghUPMC
Clinical and Translational Science Institute, University of PittsburghCTSI
Document Type: Article
Publication Stage: Final
Source: Scopus
Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity
(2023) Molecular Metabolism, 68, art. no. 101664, .
Brazill, J.M.a , Shin, D.a , Magee, K.a , Majumdar, A.a , Shen, I.R.a , Cavalli, V.b c d , Scheller, E.L.a c e f
a Department of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, United States
b Department of Neuroscience, Washington University, Saint Louis, MO, United States
c Center of Regenerative Medicine, Washington University School of Medicine, Saint Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, United States
e Department of Cell Biology and Physiology, Washington University, Saint Louis, MO, United States
f Department of Biomedical Engineering, Washington University, Saint Louis, MO, United States
Abstract
Objective: Obesity and nutrient oversupply increase mammalian target of rapamycin (mTOR) signaling in multiple cell types and organs, contributing to the onset of insulin resistance and complications of metabolic disease. However, it remains unclear when and where mTOR activation mediates these effects, limiting options for therapeutic intervention. The objective of this study was to isolate the role of constitutive mTOR activation in Nav1.8-expressing peripheral neurons in the onset of diet-induced obesity, bone loss, and metabolic disease. Methods: In humans, loss of function mutations in tuberous sclerosis complex 2 (TSC2) lead to maximal constitutive activation of mTOR. To mirror this in mice, we bred Nav1.8-Cre with TSC2fl/fl animals to conditionally delete TSC2 in Nav1.8-expressing neurons. Male and female mice were studied from 4- to 34-weeks of age and a subset of animals were fed a high-fat diet (HFD) for 24-weeks. Assays of metabolism, body composition, bone morphology, and behavior were performed. Results: By lineage tracing, Nav1.8-Cre targeted peripheral sensory neurons, a subpopulation of postganglionic sympathetics, and several regions of the brain. Conditional knockout of TSC2 in Nav1.8-expressing neurons (Nav1.8-TSC2KO) selectively upregulated neuronal mTORC1 signaling. Male, but not female, Nav1.8-TSC2KO mice had a 4–10% decrease in body size at baseline. When challenged with HFD, both male and female Nav1.8-TSC2KO mice resisted diet-induced gains in body mass. However, this did not protect against HFD-induced metabolic dysfunction and bone loss. In addition, despite not gaining weight, Nav1.8-TSC2KO mice fed HFD still developed high body fat, a unique phenotype previously referred to as ‘normal weight obesity’. Nav1.8-TSC2KO mice also had signs of chronic itch, mild increases in anxiety-like behavior, and sex-specific alterations in HFD-induced fat distribution that led to enhanced visceral obesity in males and preferential deposition of subcutaneous fat in females. Conclusions: Knockout of TSC2 in Nav1.8+ neurons increases itch- and anxiety-like behaviors and substantially modifies fat storage and metabolic responses to HFD. Though this prevents HFD-induced weight gain, it masks depot-specific fat expansion and persistent detrimental effects on metabolic health and peripheral organs such as bone, mimicking the ‘normal weight obesity’ phenotype that is of growing concern. This supports a mechanism by which increased neuronal mTOR signaling can predispose to altered adipose tissue distribution, adipose tissue expansion, impaired peripheral metabolism, and detrimental changes to skeletal health with HFD – despite resistance to weight gain. © 2022 The Authors
Author Keywords
Anxiety; Bone; High fat diet; Itch; mTOR; Nav1.8; Neurometabolism; Normal weight obesity; Sensory nerve; Skinny fat
Funding details
National Institutes of HealthNIHP30-AR074992, R56-AR081251, T32-AR060719
Musculoskeletal Research Center, Washington University in St. LouisMRCP30-DK020579
Department of Medicine, Georgetown University
Document Type: Article
Publication Stage: Final
Source: Scopus
A pleiotropic chemoreceptor facilitates the production and perception of mating pheromones
(2023) iScience, 26 (1), art. no. 105882, .
Vernier, C.L.a , Leitner, N.a , Zelle, K.M.a , Foltz, M.a , Dutton, S.a , Liang, X.b , Halloran, S.c , Millar, J.G.c , Ben-Shahar, Y.a
a Department of Biology, Washington University in Saint Louis, 1 Brookings Drive, Saint Louis, MO 63130, United States
b Department of Neuroscience, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c Department of Entomology, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, United States
Abstract
Optimal mating decisions depend on the robust coupling of signal production and perception because independent changes in either could carry a fitness cost. However, since the perception and production of mating signals are often mediated by different tissues and cell types, the mechanisms that drive and maintain their coupling remain unknown for most animal species. Here, we show that in Drosophila, behavioral responses to, and the production of, a putative inhibitory mating pheromone are co-regulated by Gr8a, a member of the Gustatory receptor gene family. Specifically, through behavioral and pheromonal data, we found that Gr8a independently regulates the behavioral responses of males and females to a putative inhibitory pheromone, as well as its production in the fat body and oenocytes of males. Overall, these findings provide a relatively simple molecular explanation for how pleiotropic receptors maintain robust mating signaling systems at the population and species levels. © 2022 The Authors
Author Keywords
Biochemistry; Biological sciences; Ecological biochemistry
Funding details
National Science FoundationNSF1322783, 1707221, 1754264
National Institutes of HealthNIHNS089834, P40OD018537
Cornell UniversityCU
University of TorontoU of T
Document Type: Article
Publication Stage: Final
Source: Scopus
ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy
(2023) Science (New York, N.Y.), 379 (6628), p. eadd1236.
Seo, D.-O.a , O’Donnell, D.b , Jain, N.a , Ulrich, J.D.a , Herz, J.c d , Li, Y.e , Lemieux, M.c d , Cheng, J.b , Hu, H.a , Serrano, J.R.a , Bao, X.a , Franke, E.a , Karlsson, M.b , Meier, M.b , Deng, S.b , Desai, C.b , Dodiya, H.f , Lelwala-Guruge, J.b , Handley, S.A.d , Kipnis, J.c d , Sisodia, S.S.f , Gordon, J.I.b d , Holtzman, D.M.a g
a Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
b Edison Family Center for Genome Sciences and Systems Biology and the Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO, United States
c Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurobiology, University of Chicago, Chicago, IL, United States
g Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Tau-mediated neurodegeneration is a hallmark of Alzheimer’s disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex- and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.
Document Type: Article
Publication Stage: Final
Source: Scopus
A single-cell massively parallel reporter assay detects cell-type-specific gene regulation
(2023) Nature Genetics, .
Zhao, S.a b d , Hong, C.K.Y.a b , Myers, C.A.c , Granas, D.M.a b , White, M.A.a b , Corbo, J.C.c , Cohen, B.A.a b
a Edison Family Center for Systems Biology and Genome Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Ginkgo Bioworks, Boston, MA, United States
Abstract
Massively parallel reporter gene assays are key tools in regulatory genomics but cannot be used to identify cell-type-specific regulatory elements without performing assays serially across different cell types. To address this problem, we developed a single-cell massively parallel reporter assay (scMPRA) to measure the activity of libraries of cis-regulatory sequences (CRSs) across multiple cell types simultaneously. We assayed a library of core promoters in a mixture of HEK293 and K562 cells and showed that scMPRA is a reproducible, highly parallel, single-cell reporter gene assay that detects cell-type-specific cis-regulatory activity. We then measured a library of promoter variants across multiple cell types in live mouse retinas and showed that subtle genetic variants can produce cell-type-specific effects on cis-regulatory activity. We anticipate that scMPRA will be widely applicable for studying the role of CRSs across diverse cell types. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
National Institutes of HealthNIHR01 EY030075, R01 GM092910, R01 GM140711
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A pilot randomized controlled trial of a cognitive-behavioral therapy-guided self-help mobile app for the post-acute treatment of anorexia nervosa: A registered report
(2023) International Journal of Eating Disorders, .
Fitzsimmons-Craft, E.E.a , Laboe, A.A.a , McGinnis, C.a , Firebaugh, M.-L.a , Shah, J.a , Wallendorf, M.b , Jacobi, C.c , Bardone-Cone, A.M.d , Pike, K.M.e , Taylor, C.B.f g , Wilfley, D.E.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
d Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
e Department of Psychiatry, Columbia University, New York, NY, United States
f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
g Center for m2Health, Palo Alto University, Palo Alto, CA, United States
Abstract
Introduction: Relapse following acute treatment for anorexia nervosa (AN) is common. Evidence suggests cognitive-behavioral therapy (CBT) may be useful in the post-acute period, but few patients have access to trained providers. mHealth technologies have potential to increase access to high-quality care for AN, including in the post-acute period. The aim of this study is to estimate the preliminary feasibility and effectiveness of a CBT-based mobile intervention plus treatment as usual (TAU), offered with and without an accompanying social networking feature. Method: In the current pilot randomized controlled trial, women with AN who have been discharged from acute treatment in the past 2 months (N = 90) will be randomly assigned to a CBT-based mobile intervention plus treatment as usual (TAU), a CBT-based mobile intervention including social networking plus TAU, or TAU alone. We will examine feasibility, acceptability, and preliminary effectiveness of the three conditions in terms of reducing eating disorder psychopathology, reducing frequency of eating disorder behaviors, achieving weight maintenance, reducing depression and suicidal ideation, and reducing clinical impairment. We will examine rehospitalization and full recovery rates in an exploratory fashion. We will also examine whether the mobile intervention and social networking feature change the proposed targets and whether changes in targets are associated with benefit, as well as conduct exploratory analyses to identify within-mobile intervention predictors and moderators of outcome. Discussion: Ultimately, this research may lead to increased access to evidence-based treatment for individuals with AN and prevention of the extreme negative consequences that can result from this serious disorder. Public Significance: Relapse after acute treatment for anorexia nervosa is common, and few patients have access to trained providers to support them following acute care. This study will pilot a coached mobile app, including a social networking component, for this population. If ultimately successful, our approach could greatly increase access to evidence-based treatment for individuals with anorexia nervosa and ultimately prevent the extreme negative consequences that can result from this serious disorder. © 2023 Wiley Periodicals LLC.
Author Keywords
anorexia nervosa; eating disorders; mobile intervention; post-acute treatment; social networking
Funding details
National Institute of Mental HealthNIMH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Is parent personality associated with adolescent outcomes for their child? A response surface analysis approach
(2023) Infant and Child Development, .
Wright, A.J., Jackson, J.J.
Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
A parent has immense control over the experiences of their offspring. Given that personality is associated with important life outcomes—mediated through decision-making processes—it is likely that parental personality impacts their child’s life outcomes. While “compensatory” influences from another person have been identified in romantic partners, the impact of parent’s personality on their child’s outcomes has not been thoroughly examined. Using a response surface analysis approach, we will look at the associations of adolescent personality with the personality of their parents for the prediction of adolescent outcomes (Ndyads = 9395). Parent personality predicted outcomes for their child above and beyond their child’s traits. There were few instances of child–parent personality interactions, suggesting the mechanisms linking child and parent traits to child outcomes are largely independent. Findings suggest parents’ personalities offer a unique influence on the outcomes for children while they develop and navigate through adolescence. Highlights: This paper investigated if parental Big Five personality traits predicted outcomes for their child in adolescence, above and beyond the child’s own traits. Response surface analyses indicated that parent personality does predict outcomes for their adolescent child, with few interaction or similarity effects emerging. These findings suggest the Big Five traits of parents are impactful in the child and parent relationship and can uniquely influence outcomes for the child above and beyond their own traits. © 2023 John Wiley & Sons Ltd.
Author Keywords
adolescence; big five; child and parent relationship; personality; response surface analysis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The association between different dimensions of social capital and cognition among older adults in China
(2023) Journal of Affective Disorders Reports, 11, art. no. 100466, .
Liu, X.a , Wang, Q.b c , Liu, S.d , Liu, B.e f , Kong, F.e f , Zhang, W.e f , Sun, Q.e f , Li, H.e f
a Jinan Municipal Center for Disease Control and Prevention, China
b School of Public Health, Peking University, Beijing, 100871, China
c Brown School, Washington University in St. Louis, St. Louis, MO 63130, United States
d Center of Health System and Policy, Institute of Medical Information & Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100020, China
e Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Shandong, Jinan, China
f National Health Commission (NHC) Key Lab of Health Economics and Policy Research, Shandong University, Shandong, Jinan, China
Abstract
Background: Social capital is a multidimensional concept including social trust, social support, social participation, and reciprocity, and each dimension may be associated with the cognition of older adults differently. The existing research on social capital and cognition rarely constructs a comprehensive social capital framework and compares the association between the cognition and multiple dimensions of social capital. Objective: To determine whether four social capital domains have different associations with cognition among older adults in China. Methods: Baseline and four-year follow-up data (N = 6291) from community-dwelling participants aged ≥55 years at baseline from CHARLS were used. Generalized linear regression was conducted to assess the association between four dimensions of social capital at baseline and cognition at four-year follow-up of all samples, controlling for baseline cognitive scores. Results: Both financial support (β = 0.177, p = 0.013) and reciprocity (β = 0.280, p = 0.022) at baseline were associated with better executive function four years later, and social participation (β = 0.123, p = 0.004) at baseline was associated with better episodic memory after four years. Age, gender, education and hukou modified the association between social capital and cognition (p < 0.05). Conclusion: Financial support, reciprocity and social participation was associated with cognition among Chinese older adults to different extent. © 2023 The Author(s)
Author Keywords
Cognition; Older adults; Reciprocity; Social capital; Social participation; Social support; Social trust
Document Type: Article
Publication Stage: Final
Source: Scopus
Monosynaptic restriction of the anterograde herpes simplex virus strain H129 for neural circuit tracing
(2023) Journal of Comparative Neurology, .
Fischer, K.B.a , Collins, H.K.a , Pang, Y.a , Roy, D.S.b , Zhang, Y.c , Feng, G.b c , Li, S.-J.d , Kepecs, A.e , Callaway, E.M.a
a Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La JollaCA, United States
b Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
c Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at MIT, Cambridge, MA, United States
d Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
e Departments of Neuroscience and Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Identification of synaptic partners is a fundamental task for systems neuroscience. To date, few reliable techniques exist for whole brain labeling of downstream synaptic partners in a cell-type-dependent and monosynaptic manner. Herein, we describe a novel monosynaptic anterograde tracing system based on the deletion of the gene UL6 from the genome of a cre-dependent version of the anterograde Herpes Simplex Virus 1 strain H129. Given that this knockout blocks viral genome packaging and thus viral spread, we reasoned that co-infection of a HSV H129 ΔUL6 virus with a recombinant adeno-associated virus expressing UL6 in a cre-dependent manner would result in monosynaptic spread from target cre-expressing neuronal populations. Application of this system to five nonreciprocal neural circuits resulted in labeling of neurons in expected projection areas. While some caveats may preclude certain applications, this system provides a reliable method to label postsynaptic partners in a brain-wide fashion. © 2023 Wiley Periodicals LLC.
Funding details
National Science FoundationNSFIOS‐1707261
National Institutes of HealthNIHEY022577, MH063912, U01MH114819
National Institute of Neurological Disorders and StrokeNINDSR01NS075531
Massachusetts Institute of TechnologyMIT
Broad Institute
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Semiautomated analysis of an optical ATP indicator in neurons
(2022) Neurophotonics, 9 (4), art. no. 041410, .
Dehkharghanian, T.a , Hashemiaghdam, A.b , Ashrafi, G.b
a McMaster University, Faculty of Health Sciences, Hamilton, ON, Canada
b Washington University School of Medicine in St. Louis, Needleman Center for Neurometabolism and Axonal Therapeutics, Department of Cell Biology and Physiology, Department of Genetics, St. Louis, MO, United States
Abstract
Significance: The firefly enzyme luciferase has been used in a wide range of biological assays, including bioluminescence imaging of adenosine triphosphate (ATP). The biosensor Syn-ATP utilizes subcellular targeting of luciferase to nerve terminals for optical measurement of ATP in this compartment. Manual analysis of Syn-ATP signals is challenging due to signal heterogeneity and cellular motion in long imaging sessions. Here, we have leveraged machine learning tools to develop a method for analysis of bioluminescence images. Aim: Our goal was to create a semiautomated pipeline for analysis of bioluminescence imaging to improve measurements of ATP content in nerve terminals. Approach: We developed an image analysis pipeline that applies machine learning toolkits to distinguish neurons from background signals and excludes neural cell bodies, while also incorporating user input. Results: Side-by-side comparison of manual and semiautomated image analysis demonstrated that the latter improves precision and accuracy of ATP measurements. Conclusions: Our method streamlines data analysis and reduces user-introduced bias, thus enhancing the reproducibility and reliability of quantitative ATP imaging in nerve terminals. © 2022 The Authors. Published by SPIE under a Creative Commons Attribution 4.0 International License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
Author Keywords
ATP; bioluminescence; image analysis; machine learning; nerve terminals
Document Type: Article
Publication Stage: Final
Source: Scopus
Structure-based design of bitopic ligands for the µ-opioid receptor
(2022) Nature, .
Faouzi, A.a , Wang, H.b , Zaidi, S.A.c , DiBerto, J.F.d , Che, T.a d , Qu, Q.b e , Robertson, M.J.b e , Madasu, M.K.a , El Daibani, A.a , Varga, B.R.a , Zhang, T.f , Ruiz, C.g , Liu, S.h , Xu, J.h , Appourchaux, K.a , Slocum, S.T.d , Eans, S.O.i , Cameron, M.D.g , Al-Hasani, R.a , Pan, Y.X.f h , Roth, B.L.d , McLaughlin, J.P.i , Skiniotis, G.b e , Katritch, V.c , Kobilka, B.K.b , Majumdar, S.a
a Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St Louis, MO, United States
b Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, United States
c Department of Quantitative and Computational Biology, Department of Chemistry, Bridge Institute and Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, United States
d Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
e Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, United States
f Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
g Department of Chemistry, Scripps Research, Jupiter, FL, United States
h Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, United States
i Department of Pharmacodynamics, University of Florida, Gainesville, FL, United States
Abstract
Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose1. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment—one (C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
National Institutes of HealthNIHP01DA035764, R00DA038725, R01DA007242, R01DA042888, R21DA048650, R33045884, R33DA038858, R37DA036246
National Institute of Mental HealthNIMHHHSN-271-2018-00023-C
National Cancer InstituteNCIP30 CA008748
Brain and Behavior Research FoundationBBRF
American Heart AssociationAHA
G. Harold and Leila Y. Mathers Charitable Foundation
Stanford UniversitySU
SLAC National Accelerator LaboratorySLAC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Cortex-wide response mode of VIP-expressing inhibitory neurons by reward and punishment
(2022) eLife, 11, art. no. e78815, .
Szadai, Z.a b c d , Pi, H.-J.e f , Chevy, Q.e g , Ócsai, K.b d h i , Albeanu, D.F.e , Chiovini, B.a , Szalay, G.a , Katona, G.b , Kepecs, A.e g , Rózsa, B.a d
a Laboratory of 3D functional network and dendritic imaging, Institute of Experimental Medicine, Budapest, Hungary
b MTA-PPKE ITK-NAP B – 2p Measurement Technology Group, The Faculty of Information Technology, Pázmány Péter Catholic University, Budapest, Hungary
c János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary
d BrainVisionCenter, Budapest, Hungary
e Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
f Volen Center for Complex Systems, Biology Department, Brandeis University, Waltham, United States
g Departments of Neuroscience and Psychiatry, Washington University School of Medicine, St. Louis, United States
h Computational Systems Neuroscience Lab, Wigner Research Centre for Physics, Budapest, Hungary
i Department of Mathematical Geometry, Institute of Mathematics, Budapest University of Technology and Economics, Budapest, Hungary
Abstract
Neocortex is classically divided into distinct areas, each specializing in different function, but all could benefit from reinforcement feedback to inform and update local processing. Yet it remains elusive how global signals like reward and punishment are represented in local cortical computations. Previously, we identified a cortical neuron type, vasoactive intestinal polypeptide (VIP)-expressing interneurons, in auditory cortex that is recruited by behavioral reinforcers and mediates disinhibitory control by inhibiting other inhibitory neurons. As the same disinhibitory cortical circuit is present virtually throughout cortex, we wondered whether VIP neurons are likewise recruited by reinforcers throughout cortex. We monitored VIP neural activity in dozens of cortical regions using three-dimensional random access two-photon microscopy and fiber photometry while mice learned an auditory discrimination task. We found that reward and punishment during initial learning produce rapid, cortex-wide activation of most VIP interneurons. This global recruitment mode showed variations in temporal dynamics in individual neurons and across areas. Neither the weak sensory tuning of VIP interneurons in visual cortex nor their arousal state modulation was fully predictive of reinforcer responses. We suggest that the global response mode of cortical VIP interneurons supports a cell-type-specific circuit mechanism by which organism-level information about reinforcers regulates local circuit processing and plasticity. © Szadai, Pi, Chevy et al.
Funding details
VKSZ_14-1-2015-0155 KFI_16-1-2016-0177 NVKP_16-1-2016-0043
National Institutes of HealthNIHR01MH110391, R01NS075531, R01NS088661
National Alliance for Research on Schizophrenia and DepressionNARSAD
Horizon 2020 Framework ProgrammeH2020682426, 712821-NEURAM, VISGEN_734862
European Research CouncilERC
Magyar Tudományos AkadémiaMTA
Nemzeti Kutatási, Fejlesztési és Innovaciós AlapNKFIAKFI_16-1-2016-0177, VKSZ_14-1-2015-0155
1.2.1-NKP-2017–00002, GINOP_2.1.1-15-2016-00979, KFI-2018–00097, KTIA_NAP_12-2-2015-0006, NKP-2017–00001, VKE-2018–00032
Document Type: Article
Publication Stage: Final
Source: Scopus