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| Open AccessDopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo
Here, the authors report that schizophrenia risk variants mapping to a striatal dopamine-related gene set are associated with increased striatal dopamine synthesis capacity and increased striatal activity during reward anticipation in humans.
- Leonardo Sportelli
- , Daniel P. Eisenberg
- & Giulio Pergola
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Article
| Open AccessCross-modality mapping using image varifolds to align tissue-scale atlases to molecular-scale measures with application to 2D brain sections
Omics data’s diversity and high-dimensionality challenge integration across technologies and with imaging. Here, authors introduce mapping method xIV-LDDMM that estimates geometric and feature transformations to integrate tissue-scale atlases with molecular and cellular-scale data.
- Kaitlin M. Stouffer
- , Alain Trouvé
- & Michael I. Miller
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| Open AccessSingle cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity
Whether and how hypothalamic neurons can lose or change their identity in adulthood has remained elusive. Here, the authors show that mature pro-opiomelanocortin (Pomc) neurons contain invisible ‘Ghost’ subsets with atypical identities that are recruited in response to obesogenic stimuli.
- Stéphane Leon
- , Vincent Simon
- & Carmelo Quarta
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| Open AccessAbundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study
The authors uncover extensive genetic overlap across brain structure, functional connectivity, and brain tissue composition using multivariate methods. Insights gained enhance understanding of brain biology and prediction of psychiatric conditions.
- E. P. Tissink
- , A. A. Shadrin
- & O. A. Andreassen
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Article
| Open AccessUsing rare genetic mutations to revisit structural brain asymmetry
Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.
- Jakub Kopal
- , Kuldeep Kumar
- & Danilo Bzdok
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Article
| Open AccessIdentification of gene regulatory networks affected across drug-resistant epilepsies
Epilepsy is a chronic, heterogeneous disease with an urgent need for novel therapies. Here, the authors show a systematic comparison of the global molecular signature of refractory epilepsies elucidating the key mechanisms of the disease pathology.
- Liesbeth François
- , Alessia Romagnolo
- & Eleonora Aronica
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Article
| Open AccessPCDHA9 as a candidate gene for amyotrophic lateral sclerosis
Genetic mutations are found in only 15% of sporadic ALS. Here, authors identify PCDHA9 as a candidate ALS gene and elucidate detailed underlying pathogenesis using mice with Pcdhα9 mutations that develop typical ALS phenotype and hallmark pathology.
- Jie Zhong
- , Chaodong Wang
- & Zhiheng Xu
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Article
| Open AccessmicroRNA-33 controls hunger signaling in hypothalamic AgRP neurons
AgRP neurons regulate feeding behavior by promoting signals of hunger. Here, the authors show that miR-33, represses the activity of AgRP neurons, and selective loss of miR-33 in AgRP neurons promotes obesity and metabolic dysfunction in mice.
- Nathan L. Price
- , Pablo Fernández-Tussy
- & Carlos Fernández-Hernando
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Article
| Open AccessBHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer’s disease and other disorders of lipid-rich tissues
Factors regulating lipid and lysosomal clearance in microglia and peripheral macrophage are not known. Here, authors nominate and validate transcription factors BHLHE40 and BHLHE41 as regulators of these processes in health and disease.
- Anna Podleśny-Drabiniok
- , Gloriia Novikova
- & Alison Mary Goate
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Article
| Open AccessGenetic architecture of the structural connectome
The structural connectome is the complete set of anatomical connections between brain cells. Here, the authors perform a genome-wide association study of white-matter structural connectivity in the human brain, finding 30 variants influencing the density of myelinated connections between brain regions.
- Michael Wainberg
- , Natalie J. Forde
- & Shreejoy J. Tripathy
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Article
| Open AccessBrain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation
How early life experience impacts adult behavior is unclear. Here, authors show that maternal immune activation remodels mouse brain methylome and selectively regulates neuronal activity genes, resulting in anxiety- and depression-like behaviors.
- Li Ma
- , Feng Wang
- & Jian-Fu Chen
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Article
| Open AccessThe genetic relationships between brain structure and schizophrenia
Schizophrenia is considered a brain disorder. Here, authors show genetic overlap between brain structure and schizophrenia that was strongest in the hubs of structural covariance networks and concentrated three chromosomal regions.
- Eva-Maria Stauffer
- , Richard A. I. Bethlehem
- & Edward T. Bullmore
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Article
| Open AccessMolecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years
A comprehensive multi-omic analysis of the EPISTOP trial for Tuberous Sclerosis Complex (TSC). was performed. Here, authors show many differences in serum proteins and metabolites, and blood RNA species, including associations with seizure development.
- Franz Huschner
- , Jagoda Głowacka-Walas
- & David J. Kwiatkowski
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| Open AccessCross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy
Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.
- Yuhao Min
- , Xue Wang
- & Nilüfer Ertekin-Taner
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Article
| Open AccessMapping the spatial transcriptomic signature of the hippocampus during memory consolidation
Transcriptional events are critical for hippocampus-dependent long-term memory storage. Here, the authors utilize spatial transcriptomics to elucidate localized gene expression patterns across hippocampal subregions during memory consolidation.
- Yann Vanrobaeys
- , Utsav Mukherjee
- & Snehajyoti Chatterjee
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| Open AccessSpatial organization of the mouse retina at single cell resolution by MERFISH
Many molecularly classified retinal cell types lack spatial information. Here, authors used MERFISH to create a spatial atlas of the mouse retina, leveraging co-embedding with scRNA-seq to explore spatially dependent gene expression in retinal cell subtypes.
- Jongsu Choi
- , Jin Li
- & Rui Chen
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Article
| Open AccessAssociation between vmPFC gray matter volume and smoking initiation in adolescents
The relationship between brain development and smoking behaviour is not well understood. Here, the authors show an association between volume of the left ventromedial prefrontal cortex and smoking initiation in adolescents.
- Shitong Xiang
- , Tianye Jia
- & Jianfeng Feng
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Article
| Open AccessCellular profiling of a recently-evolved social behavior in cichlid fishes
This study links the genomic basis of behavioral variation to specific cell populations in the brain. Here, authors find evidence for involvement of neural stem cells in the evolution and expression of bower-building behavior in cichlid fishes.
- Zachary V. Johnson
- , Brianna E. Hegarty
- & Jeffrey T. Streelman
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Article
| Open AccessProfiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex
Opioid use disorder (OUD) is influenced by genetic and environmental factors. Here, authors use a multi-omics approach to reveal DNA hydroxymethylation as an important gene regulatory mechanism for OUD in the human brain.
- Gregory Rompala
- , Sheila T. Nagamatsu
- & Janitza L. Montalvo-Ortiz
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Article
| Open AccessGenes associated with cognitive ability and HAR show overlapping expression patterns in human cortical neuron types
Using transcriptomic data from human brain cells, the authors show that the expression patterns of the genes implicated in human cognition and brain evolution overlap in specific neuron types, and relate to cellular function and structure.
- Stan L. W. Driessens
- , Anna A. Galakhova
- & Natalia A. Goriounova
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| Open AccessSpatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury
To understand complexity of cellular function, multiple phenotypic readouts are needed. Here, authors devised an approach integrating location, transcriptome, ultrastructure, and lipid content to characterize single-cell states after brain injury.
- Peter Androvic
- , Martina Schifferer
- & Ozgun Gokce
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Article
| Open AccessSingle-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
Mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) cause autosomal dominant AD (ADAD). Here, the authors perform single-nucleus RNA-sequencing of ADAD and other disease risk modifying variant carriers and report altered expression states of specific brain cell types.
- Logan Brase
- , Shih-Feng You
- & Oscar Harari
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| Open AccessThe basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice
While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here, authors show the critical role of the BLA-ACC pathway in pain and emotional processing, and their comorbidity.
- Léa J. Becker
- , Clémentine Fillinger
- & Ipek Yalcin
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| Open AccessBrain-wide and cell-specific transcriptomic insights into MRI-derived cortical morphology in macaque monkeys
A comprehensive anatomically-defined atlas of brain transcriptomics in macaques is still lacking. Here, the authors generate complementary bulk RNA-seq and snRNA-seq datasets from cynomolgus macaques to examine the link between brain-wide gene expression and regional variation in morphometry.
- Tingting Bo
- , Jie Li
- & Zheng Wang
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Article
| Open AccessCell type diversity in a developing octopus brain
The brain cell types of Octopus vulgaris that control their sophisticated behavioral repertoire are still unknown. Here, authors use single-cell transcriptomics to profile neuronal and glial cell types and compare cell type relationships within the octopus brain and across species.
- Ruth Styfhals
- , Grygoriy Zolotarov
- & Eve Seuntjens
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| Open AccessAscertaining cells’ synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries
Synaptic connections are critical for brain function but are hard to measure systematically. Here, authors present a method which uses rabies virus barcoding and single-cell RNAseq to parallelize monosynaptic network reconstruction from molecularly-profiled single cells.
- Arpiar Saunders
- , Kee Wui Huang
- & Steven A. McCarroll
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Article
| Open AccessGenetic map of regional sulcal morphology in the human brain from UK biobank data
Genetic associations with particular patterns of brain folding may provide insight into brain development and function. Here, the authors identify and replicate 388 genetic associations with brain sulcal morphology across 40,169 UK Biobank MRI scans, revealing insights into the processes guiding cortical development and genetic correlations with neuropsychiatric phenotypes.
- Benjamin B. Sun
- , Stephanie J. Loomis
- & Christopher D. Whelan
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Article
| Open AccessDistributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders
The hippocampus has been associated with memory traits and a variety of neurodegenerative and psychiatric disorders. Here, the authors have done a multivariate GWAS revealing 177 genetic loci, and overlap with various brain disorders may suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.
- Shahram Bahrami
- , Kaja Nordengen
- & Tobias Kaufmann
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Article
| Open AccessAssociation between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder
Gene expression patterns have been associated with functional activity patterns in the brain. Here the authors determine how gene expression patterns in the human brain supports brain phenotypes obtained from resting state fMRI imaging, identifying brain regions and genes relevant to autism.
- Stefano Berto
- , Alex H. Treacher
- & Genevieve Konopka
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Article
| Open AccessSerotonin and dopamine modulate aging in response to food odor and availability
This report finds that dietary restriction, the most extensively studied anti-aging intervention, can be mimicked by blocking food odour signaling and identifies a neural network of food perception that functions through serotonin and dopamine.
- Hillary A. Miller
- , Shijiao Huang
- & Scott F. Leiser
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Article
| Open AccessTranscriptional adaptation of olfactory sensory neurons to GPCR identity and activity
Olfaction in mammals relies on a toolbox composed of a varied set of sensory neurons. Here, the authors report in mice that this olfactory neuronal diversity relies both on the chemoreceptor that each neuron expresses and on the experience of this neuron.
- Luis Flores Horgue
- , Alexis Assens
- & Ivan Rodriguez
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Article
| Open AccessExtended intergenic DNA contributes to neuron-specific expression of neighboring genes in the mammalian nervous system
A large part of noncoding DNA is intergenic regions, yet how the size of intergenic regions affects gene expression in a tissue-specific manner is unclear. Here the authors present long intergenic DNA length-dependent neural gene expression, reflecting the complexity in the mammalian nervous system.
- Ravneet Jaura
- , Ssu-Yu Yeh
- & Ho Sung Rhee
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Article
| Open AccessGenetic and phylogenetic uncoupling of structure and function in human transmodal cortex
Brain structure scaffolds intrinsic function, supporting cognition and behavioral flexibility. Here, the authors show how macroscale organization of cortical microstructure and resting-state function uncouple in transmodal cortex of humans and macaques.
- Sofie L. Valk
- , Ting Xu
- & Boris C. Bernhardt
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Article
| Open AccessMultivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain
How the tissue composition of the human brain is determined remains unclear. Here, the authors apply advanced analyses to two large imaging genetic datasets to identify and validate genetic loci that simultaneously influence multiple brain regions.
- Chun Chieh Fan
- , Robert Loughnan
- & Anders M. Dale
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Article
| Open AccessMultilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation
The genetic control underlying axon formation in neurons is unknown. Here, the authors report that neural-specific induction of TRIM46, one of the earliest axonal markers, is regulated by alternative splicing, NMD, and protein stability controls.
- John K. Vuong
- , Volkan Ergin
- & Sika Zheng
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Article
| Open AccessCMTr cap-adjacent 2′-O-ribose mRNA methyltransferases are required for reward learning and mRNA localization to synapses
The two cap methyltransferases (CMTrs) redundantly methylate riboses of first cap adjacent nucleotides in messenger RNAs in Drosophila. Here, CMTrs are required for reward learning and localization of untranslated messenger RNAs to synapses.
- Irmgard U. Haussmann
- , Yanying Wu
- & Matthias Soller
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Article
| Open AccessAssociations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors
Schizophrenia is a complex disorder where individuals experience different symptoms and outcomes that can be captured by patterns in other diagnoses. Here the authors use computational approaches to summarize these patterns and suggest they are associated with genetic and environmental exposure.
- Morten Dybdahl Krebs
- , Gonçalo Espregueira Themudo
- & Wesley K. Thompson
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| Open AccessA C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation
A hexanucleotide repeat expansion of C9orf72 is translated to dipeptide repeat proteins in amyotrophic lateral sclerosis and frontotemporal dementia patients. Here the authors generate a C. elegans model of C9orf72-mediated ALS/FTD and show that translation initiation factor eIF2D regulates the dipeptide repeat protein expression.
- Yoshifumi Sonobe
- , Jihad Aburas
- & Paschalis Kratsios
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Article
| Open AccessA nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila
Maintaining metabolic homeostasis during feeding and fasting states is critical to animal survival. Here the authors show that Capa hormone signaling, homologs to mammalian Neuromedin U, helps control homeostasis via regulation of nutrient uptake and energy storage in Drosophila.
- Takashi Koyama
- , Selim Terhzaz
- & Kenneth V. Halberg
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Article
| Open AccessHeritability and interindividual variability of regional structure-function coupling
The relationship between the human structural and functional connectome is still not well established. Here the authors show the interindividual variability that exists in regional coupling of structural and functional connectivity across the brain, and that this is heritable.
- Zijin Gu
- , Keith Wakefield Jamison
- & Amy Kuceyeski
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Article
| Open AccessGenetic influences on hub connectivity of the human connectome
How genes sculpt the complex architecture of the human connectome remains unclear. Here, the authors show that genes preferentially influence the strength of connectivity between functionally valuable, metabolically costly connections between brain network hubs.
- Aurina Arnatkeviciute
- , Ben D. Fulcher
- & Alex Fornito
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Article
| Open AccessGenetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications
Duplication of chromosome 15q11-q13 is associated with autism spectrum disorder (ASD). Here, the authors show that in mice paternal Dup15q results in ASD-like neuronal and behavioural impairment driven by Necdin.
- Kota Tamada
- , Keita Fukumoto
- & Toru Takumi
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Article
| Open AccessNeuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.
- Benxia Hu
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessThe steroid-hormone ecdysone coordinates parallel pupariation neuromotor and morphogenetic subprograms via epidermis-to-neuron Dilp8-Lgr3 signal induction
Pupariation in Drosophila is triggered by the steroid-hormone ecdysone and requires coordination between associated behavioral and body-reshaping motor subprograms. The authors show that coordination requires ecdysone-dependent Dilp8-Lgr3 signaling between the cuticle epidermis and interneurons.
- Fabiana Heredia
- , Yanel Volonté
- & Alisson M. Gontijo
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Article
| Open AccessSatb2 neurons in the parabrachial nucleus mediate taste perception
The genetic identity of taste-responsive neurons has not been determined. The authors describe neurons in the gustatory region of the parabrachial nucleus that express the transcription factor Satb2, project to taste-associated regions, and modulate taste preferences.
- Brooke C. Jarvie
- , Jane Y. Chen
- & Richard D. Palmiter
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Article
| Open AccessModelling genetic mosaicism of neurodevelopmental disorders in vivo by a Cre-amplifying fluorescent reporter
Genetic mosaicism is frequently present in monogenic diseases of the central nervous system. Here the authors design a dual-colour reporter system that can be used to tune the degree of mosaicism in mouse models.
- Francesco Trovato
- , Riccardo Parra
- & Gian Michele Ratto
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Article
| Open AccessGenetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults
Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.
- Edith Hofer
- , Gennady V. Roshchupkin
- & Sudha Seshadri
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Article
| Open AccessThe genetic architecture of human brainstem structures and their involvement in common brain disorders
The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.
- Torbjørn Elvsåshagen
- , Shahram Bahrami
- & Tobias Kaufmann
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Article
| Open AccessUnderstanding the genetic determinants of the brain with MOSTest
Regional brain morphology has a complex genetic architecture. Here the authors present MOSTest, a multivariate statistical framework, apply it to UK Biobank data, and discover hundreds of loci associated with regional brain morphology.
- Dennis van der Meer
- , Oleksandr Frei
- & Anders M. Dale