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Article
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Neonatal brain dynamic functional connectivity in term and preterm infants and its association with early childhood neurodevelopment
Neonatal brain dynamics are not well understood. Here, the authors characterise brain transient states in neonates, and show that preterm infants display altered whole brain dynamics and an atypical repertoire of regional transient states, which are associated with behavioural outcomes at 18 months of age.
- Lucas G. S. França
- , Judit Ciarrusta
- & Dafnis Batalle
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Article
| Open Access
Brain asymmetries from mid- to late life and hemispheric brain age
The human brain is highly asymmetrical and increasingly so with age. Here the authors examine hemispheric brain age estimates, which provide additional insights into brain asymmetries.
- Max Korbmacher
- , Dennis van der Meer
- & Ivan I. Maximov
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Article
| Open Access
Structural connectome architecture shapes the maturation of cortical morphology from childhood to adolescence
Cortical morphology shows maturation during childhood and adolescence. Here the authors show this is structurally constrained by a diffusion network model and that this constraint is linked to gene expression profiles of microstructural development.
- Xinyuan Liang
- , Lianglong Sun
- & Yong He
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Article
| Open Access
A phylogenetically-conserved axis of thalamocortical connectivity in the human brain
The principles underpinning the projection patterns of the thalamus to the cortex are not well characterised. Here, the authors reveal a medial to lateral thalamic gradient of genetic and connectomic variation which aligns with an anterior to posterior cortical pattern.
- Stuart Oldham
- & Gareth Ball
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Matters Arising
| Open Access
Fluid signal suppression characteristics of 3D-FLAIR with a T2 selective inversion pulse in the skull base
- Shinji Naganawa
- , Yutaka Kato
- & Michihiko Sone
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Article
| Open Access
Transparent tissue in solid state for solvent-free and antifade 3D imaging
Current liquid-based optical clearing protocols can suffer from solvent evaporation and photobleaching. Here, the authors develop a solid high-refractive-index polymer to embed mouse and human tissues for clearing and antifade high-resolution 3D imaging.
- Fu-Ting Hsiao
- , Hung-Jen Chien
- & Shiue-Cheng Tang
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Article
| Open Access
Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice
Coagulation factor VIII deficiency in hemophilia A disrupts clotting and prolongs bleeding. Here, the authors show that vagus nerve stimulation bypasses this defect and improves hemostasis in hemophilia A mice through a mechanism requiring acetylcholine-secreting ChAT+ T lymphocytes in spleen and α7nAChR on circulating platelets.
- Carlos E. Bravo-Iñiguez
- , Jason R. Fritz
- & Jared M. Huston
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Article
| Open Access
Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis
The mechanisms that govern cell fate decisions of postmigratory cranial neural crest cells remain largely unknown. Here the authors present a spatiotemporal single-cell regulatory atlas tracking these cells’ dental lineage diversification.
- Junjun Jing
- , Jifan Feng
- & Yang Chai
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Article
| Open Access
Origins of direction selectivity in the primate retina
Neural coding for motion direction has been studied intensively in the visual cortex of non-human primates. Here, the authors establish an origin for direction selectivity in the retina of the macaque monkey.
- Yeon Jin Kim
- , Beth B. Peterson
- & Dennis M. Dacey
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Article
| Open Access
Multivariate 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 Access
Therapeutic homology-independent targeted integration in retina and liver
Limits of AAV-mediated gene therapy include targeting dominant mutations and inducing long-term transgene expression. Here, the authors show that AAV-HITI results in efficient allele-independent integration of a donor DNA in both retina and liver providing therapeutic benefit in mouse models of either a genetic form of blindness or a lysosomal storage disease, respectively.
- Patrizia Tornabene
- , Rita Ferla
- & Alberto Auricchio
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Article
| Open Access
In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration
Leber congenital amaurosis is caused by mutations in RPE65 and leads to retinal degeneration in children. Here, the authors show that in vivo base editing can prolong the survival of cone photoreceptors and rescue their function in a mouse model of the disease.
- Elliot H. Choi
- , Susie Suh
- & Krzysztof Palczewski
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Article
| Open Access
Investigation of Cas9 antibodies in the human eye
Pre-existing antibodies against Cas9 proteins represent a potential issue for gene therapies, including those targeting the eye. Here the authors assess the presence of intraocular antibodies, and show that Cas9 antibodies were prevalent in human serum but not the eye, unless prior bacterial infection occurred.
- Marcus A. Toral
- , Carsten T. Charlesworth
- & Vinit B. Mahajan
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Article
| Open Access
White matter myelination during early infancy is linked to spatial gradients and myelin content at birth
Myelination in early infancy develops at different rates. Here the authors describe this process whereby the back and top of the brain, as well as sections that are least mature at birth develop the fastest.
- Mareike Grotheer
- , Mona Rosenke
- & Kalanit Grill-Spector
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Article
| Open Access
Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness and is characterised by the accumulation of lipid deposits, called drusen. Here, the authors show that mice lacking chloride intracellular channel 4 in retinal pigment epithelium have defective lipid processing in the eye and pathological features mirroring human AMD, including drusen formation.
- Jen-Zen Chuang
- , Nan Yang
- & Ching-Hwa Sung
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Article
| Open Access
Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes
Studies in animal models have visualized drainage of interstitial or cerebrospinal fluid via lymphatic vessels, but there is limited data on in humans. Here, the authors non-invasively visualize lymphatic structures in the human brain, including evidence of lymphatic flow from cranial nerves to cervical lymph nodes, and differences by age and sex, without use of contrast agents.
- Mehmet Sait Albayram
- , Garrett Smith
- & Onder Albayram
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Article
| Open Access
PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells
The authors introduce PharmacoSTORM single-molecule imaging that uses fluorescent ligands and immunolabeling for cellular and subcellular nanoscale molecular pharmacology. They demonstrate its capabilities by visualizing cariprazine binding to D3 dopamine receptors on Islands of Calleja granule cell axons.
- Susanne Prokop
- , Péter Ábrányi-Balogh
- & István Katona
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Article
| Open Access
Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain
The first known portal system in the mammalian brain was identified in 1933. Here the authors describe a new portal system between the capillary beds of the Suprachiasmatic Nucleus master clock and a circumventricular organ, enabling humoral signals to reach targets without dilution in the systemic circulation.
- Yifan Yao
- , Alana B’nai Taub
- & Rae Silver
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Article
| Open Access
NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling.
- Seungyong Lee
- , Charles Hwang
- & Benjamin Levi
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Article
| Open Access
Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish
The gene regulatory network controlling the bifurcation of common progenitors into the neural retina and retinal-pigmented epithelium programs remains poorly understood. Here the authors study transcriptome dynamics and chromatin accessibility during this process in zebrafish, revealing network redundancy, as well as context-dependent and sequential transcription factor activity.
- Lorena Buono
- , Jorge Corbacho
- & Juan-Ramón Martínez-Morales
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Article
| Open Access
Molecular and cellular basis of acid taste sensation in Drosophila
Many animals, including mammals and insects, like slightly acidic yet dislike highly acidic foods, but how animals discriminate low from high acidity is unclear. Here the authors demonstrate that the fruit fly uses an evolutionarily conserved taste receptor to distinguish low from high concentrations of acid.
- Tingwei Mi
- , John O. Mack
- & Yali V. Zhang
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Article
| Open Access
Outcome after acute ischemic stroke is linked to sex-specific lesion patterns
Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.
- Anna K. Bonkhoff
- , Markus D. Schirmer
- & Natalia S. Rost
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Article
| Open Access
Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue
Small-angle X-ray scattering (SAXS) combines the high tissue penetration of X-rays with specificity to periodic nanostructures. The authors use SAXS tensor tomography (SAXS-TT) on intact mouse and human brain tissue samples, to quantify myelin levels and determine myelin integrity, myelinated axon orientation, and fibre tracts non-destructively.
- Marios Georgiadis
- , Aileen Schroeter
- & Markus Rudin
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Article
| Open Access
The genetic architecture of the human thalamus and its overlap with ten common brain disorders
Differences in thalamic structure have been observed in several psychiatric disorders, but the genetic overlap has not been explored. Here, the authors perform a genome-wide association study on thalamic nuclei volume and find genetic loci in common between thalamic volumes and brain disorders.
- Torbjørn Elvsåshagen
- , Alexey Shadrin
- & Tobias Kaufmann
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Article
| Open Access
Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures
The correlation between brain structural changes in major depressive disorder (MDD) and gene expression is unclear. Here, the authors explore the correlation between cell type-specific gene expression changes and cortical structural difference in individuals with major depressive disorder.
- Jiao Li
- , Jakob Seidlitz
- & Wei Liao
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Article
| Open Access
Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2
Jervell and Lange-Nielsen syndrome is characterised by congenital deafness and vestibular dysfunction, and is caused by mutations in KCNE1 or KCNQ1. Here, the authors show that gene therapy via canalostomy at early postnatal stage can preserve the morphology of inner ear and auditory and vestibular functions in a mouse model of human JLNS2.
- Xuewen Wu
- , Li Zhang
- & Xi Lin
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Article
| Open Access
The human endogenous attentional control network includes a ventro-temporal cortical node
Endogenous attention is known to be controlled by dorsal fronto-parietal brain areas. Here the authors identify a control attention area located in the temporal lobe, which is functionally distinct from surrounding areas, and is directly connected to parietal and frontal attentional regions.
- Ilaria Sani
- , Heiko Stemmann
- & Winrich A. Freiwald
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Article
| Open Access
Imaging fascicular organization of rat sciatic nerves with fast neural electrical impedance tomography
To be successful, selective neuromodulation requires a non-invasive method of imaging the fascicular anatomy of peripheral nerves. Here, the authors show the applicability and reliability of fast neural electrical impedance tomography for this purpose and provide its validation against the gold standards of invasive imaging.
- Enrico Ravagli
- , Svetlana Mastitskaya
- & David Holder
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Article
| Open Access
MEKK2 mediates aberrant ERK activation in neurofibromatosis type I
Neurofibromatosis type I (NF1) is characterized by prominent skeletal abnormalities mediated in part by aberrant ERK pathway activation due to NF1 loss-of-function. Here, the authors report the MEKK2 is a key mediator of this aberrant ERK activation and that MEKK2 inhibitors, including ponatinib, ameliorate skeletal defects in a mouse model of NF1.
- Seoyeon Bok
- , Dong Yeon Shin
- & Matthew B. Greenblatt
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Article
| Open Access
Children’s family income is associated with cognitive function and volume of anterior not posterior hippocampus
The hippocampus is thought to underlie income gaps in children’s cognition. Here, the authors find that the stress-sensitive anterior (but not posterior) hippocampus mediates income-gaps in memory and vocabulary, especially in children whose families earn ≤$75k annually.
- Alexandra L. Decker
- , Katherine Duncan
- & Donald J. Mabbott
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Article
| Open Access
The 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 Access
A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy
High resolution intravascular imaging in the brain is limited by the high tortuosity of the vasculature. Here the authors present a fiber optic imaging technology using high-frequency optical coherence tomography (HF-OCT) to provide volumetric high resolution images in the highly tortuous cerebral vasculature.
- Giovanni J. Ughi
- , Miklos G. Marosfoi
- & Ajit S. Puri
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Article
| Open Access
Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity
Mutations in human PIEZO2, encoding for a mechanosensitive ion channel, lead to skeletal abnormalities including scoliosis and hip dysplasia. Here, the authors show that deletion of Piezo2 in proprioceptive neurons, but not in skeletal lineages, recapitulated the human phenotype in mice.
- Eran Assaraf
- , Ronen Blecher
- & Elazar Zelzer
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Article
| Open Access
Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage
Extravasated erythrocytes in cerebrospinal fluid (CSF) contribute to the pathogenesis of subarachnoid haemorrhage (SAH). Here, the authors show that meningeal lymphatics drain extravasated erythorcytes and that blockage of this drainage aggravates SAH severity.
- Jinman Chen
- , Linmei Wang
- & Yongjun Wang
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Article
| Open Access
The visual word form area (VWFA) is part of both language and attention circuitry
The visual word form area (VWFA) is a brain region associated with written language, but it has also been linked to visuospatial attention. Here, the authors reveal distinct structural and functional circuits linking VWFA with language and attention networks, and demonstrate that these circuits separately predict language and attention abilities.
- Lang Chen
- , Demian Wassermann
- & Vinod Menon
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Article
| Open Access
First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound
MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.
- Agessandro Abrahao
- , Ying Meng
- & Lorne Zinman
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Perspective
| Open Access
A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration
No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.
- James T. Handa
- , Cathy Bowes Rickman
- & Lindsay A. Farrer
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Article
| Open Access
mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4
Denervation leads to muscle atrophy and neuromuscular endplate remodeling. Here, the authors show that a balanced activation of mTORC1 contributes to the dynamic regulation of autophagic flux in denervated muscle and that activation of PKB/Akt promotes the nuclear import of HDAC4, which is essential for endplate maintenance upon nerve injury
- Perrine Castets
- , Nathalie Rion
- & Markus A. Rüegg
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Article
| Open Access
Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation
Stimulation of peripheral nerve activity may be used to treat metabolic and inflammatory disorders, but current approaches need implanted devices. Here, the authors present a non-invasive approach, and show that ultrasound-mediated stimulation can be targeted to specific sub-organ locations in preclinical models and alter the response of metabolic and inflammatory neural pathways.
- Victoria Cotero
- , Ying Fan
- & Christopher Puleo
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Article
| Open Access
Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders
Mutations in the mechanotransduction channel component TMC1/2 cause deafness. Here, the authors use a synthetic AAV to replace TMC1 and 2 in the inner ear and show restoration of cochlear and vestibular function, of neuronal reponses in the auditory cortex and of hearing and balance in mice.
- Carl A. Nist-Lund
- , Bifeng Pan
- & Jeffrey R. Holt
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Article
| Open Access
HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns
The authors have previously shown that membrane voltage can influence embryonic patterning during development. Here, the authors computationally model how nicotine disrupts Xenopus embryogenesis by perturbing voltage gradients, and rescue nicotine-inducted defects with HCN2 channel expression.
- Vaibhav P. Pai
- , Alexis Pietak
- & Michael Levin
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Article
| Open Access
Müller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture
Müller glia are a type of retinal glial cell important for maintaining retinal structure and implicated in response to retinal damage. Here the authors identify Brevican, a chondroitin sulfate proteoglycan, as a microRNA-modulated regulator of Müller glia function.
- Stefanie G. Wohl
- , Nikolas L. Jorstad
- & Thomas A. Reh
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Article
| Open Access
Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice
It is believed that the bulk of cerebrospinal fluid (CSF) drains through arachnoid projections from the subarachnoid space to the dural venous sinuses. Here the authors show that the major outflow pathway for CSF in mice are lymphatic vessels and that this drainage decreases as the mice age.
- Qiaoli Ma
- , Benjamin V. Ineichen
- & Steven T. Proulx
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Article
| Open Access
The challenge of mapping the human connectome based on diffusion tractography
Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.
- Klaus H. Maier-Hein
- , Peter F. Neher
- & Maxime Descoteaux
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Article
| Open Access
Layer- and cell type-selective co-transmission by a basal forebrain cholinergic projection to the olfactory bulb
Cholinergic neurons innervate multiple layers in the main olfactory bulb but the precise circuitry of this input is not known. Here the authors show that VGLUT3+ cholinergic neurons selectively innervate deep short axon cells in specific layers and elicit robust monosynaptic GABAergic and nicotinic postsynaptic currents.
- Daniel T. Case
- , Shawn D. Burton
- & Rebecca P. Seal
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Article
| Open Access
Cerebral complexity preceded enlarged brain size and reduced olfactory bulbs in Old World monkeys
The evolution of the brain in Old World monkeys (cercopithecoids) is poorly understood. Here the authors describe a complete endocast of Victoriapithecus, a 15 Myr old cercopithecoid, which shows that the brain size was much smaller and the olfactory bulbs much larger than in any extant catarrhine primate.
- Lauren A. Gonzales
- , Brenda R. Benefit
- & Fred Spoor
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Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis
The transcriptional regulation of morphogenetic effectors during eye development is poorly understood. Here, the authors show that transcription of an endocytosis regulator Opois crucial for the neural retina development in zebrafish and activated by the interaction of the transcription factor Vsx2 and retinal enhancer H6_10137.
- Ines Gago-Rodrigues
- , Ana Fernández-Miñán
- & Juan R. Martinez-Morales
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Local endocytosis triggers dendritic thinning and pruning in Drosophila sensory neurons
During development, neurons prune their axons and dendrites to eliminate excessive or inappropriate connections initially formed but the mechanistic details of the pruning process are not completely understood. Here the authors visualize pruning events in dendritic branches in Drosophilaand study the role of calcium transients and endocytosis in this process.
- Takahiro Kanamori
- , Jiro Yoshino
- & Kazuo Emoto
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Article
| Open Access
Sensory integration dynamics in a hierarchical network explains choice probabilities in cortical area MT
The activity of sensory neurons can be correlated with perceptual decisions and this effect may provide insights into how sensory information is processed during perceptual tasks. Here the authors develop a network model of sensory and decision-making areas and propose that the dynamics across the network hierarchy explains the choice probabilities.
- Klaus Wimmer
- , Albert Compte
- & Jaime de la Rocha
Decomposing cortical activity through neuronal tracing connectome-eigenmodes in marmosets