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| Open AccessTopoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity
Topoisomerase 3β (Top3β) solves topological stress in DNA or RNA metabolism and its mutations are linked to mental disorders. Here, the authors describe transcriptional and behavioural impairments in Top3β-knockout mice and show that these are linked to impaired neurogenesis and synaptic plasticity.
- Yuyoung Joo
- , Yutong Xue
- & Weidong Wang
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Article
| Open AccessSIRT1 accelerates the progression of activity-based anorexia
Anorexia nervosa is an eating disorder characterized by fear of gaining weight that can lead to serious complications. Here the authors show that inhibition of SIRT1 is protective against the onset and progression of anorectic behavior in an activity-based anorexia model, suggesting SIRT1 could be a potential therapeutic target.
- Timothy M. Robinette
- , Justin W. Nicholatos
- & Sergiy Libert
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| Open AccessWeaker neural suppression in autism
Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.
- Michael-Paul Schallmo
- , Tamar Kolodny
- & Scott O. Murray
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| Open AccessA phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Depression is correlated with many brain-related traits. Here, Shen et al. perform phenome-wide association studies of a depression polygenic risk score (PRS) and find associations with 51 behavioural and 26 neuroimaging traits which are further followed up on using Mendelian randomization and mediation analyses.
- Xueyi Shen
- , David M. Howard
- & Andrew M. McIntosh
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| Open AccessA double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms
Low-grade systemic inflammation and stress increase vulnerability to neuropsychiatric disorders. Here, the authors show that inflammation and stress-induced changes in higher order cognitive networks increase vulnerability to posttraumatic stress disorder.
- Jungyoon Kim
- , Sujung Yoon
- & In Kyoon Lyoo
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| Open AccessIncreased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
Common variants identified by large-scale genomewide association studies cannot account fully account for the heritability of schizophrenia (SCZ). Here, the authors report high-coverage whole-genome sequencing of 1162 SCZ cases and 936 controls and explore the contribution of different types of variants to SCZ.
- Matthew Halvorsen
- , Ruth Huh
- & Jin P. Szatkiewicz
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Article
| Open AccessGenome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration
Vitamin D is a precursor of the steroid hormone 1,25-dihydroxyvitamin D3, and its deficiency is associated with many adverse health outcomes. Here, Revez et al. perform a genome-wide association study for circulating 25-hydroxyvitamin D in 417,580 individuals and test for potential causal relationships with other traits using Mendelian randomization.
- Joana A. Revez
- , Tian Lin
- & John J. McGrath
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| Open AccessMetagenome-wide association of gut microbiome features for schizophrenia
Gut microbiome has been linked to neurogenerative diseases. Here, the authors present a metagenome-wide association study of schizophrenia (SZ) in human cohorts and identify SZ-associated specific gut-brain functional modules and pathways including SCFAs and neurotransmitters.
- Feng Zhu
- , Yanmei Ju
- & Xiancang Ma
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Article
| Open AccessA specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction
Food addiction is linked to obesity and eating disorders. In a mouse model of food addiction, the authors show that a medial prefrontal cortex-nucleus accumbens pathway is involved in vulnerability and resilience against the development of food addiction-like behavior.
- Laura Domingo-Rodriguez
- , Inigo Ruiz de Azua
- & Rafael Maldonado
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| Open AccessPosterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect
Projections from the anterior and posterior basolateral amygdala (pBLA) to the ventral hippocampus CA1 (vCA1) are heterogenous. Here the authors show that activating the pathway from pBLA to vCA1 calbindin 1 positive neurons has an anxiolytic effect in approach-avoidance tasks in mice.
- Guilin Pi
- , Di Gao
- & Jian–Zhi Wang
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Article
| Open AccessGenetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent
Psychiatric disorders are often accompanied by alterations in BMI and body composition due to changes in eating behaviour and physical activity. Here, Hübel et al. study the genetic overlap between these traits and find that genetic correlations between psychiatric disorders and body composition are sex-specific and evident only in adulthood.
- Christopher Hübel
- , Héléna A. Gaspar
- & Gerome Breen
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| Open AccessKetamine can reduce harmful drinking by pharmacologically rewriting drinking memories
Memories linking environmental cues to alcohol reward are involved in the development and maintenance of heavy drinking. Here, the authors show that a single dose of ketamine, given after retrieval of alcohol-reward memories, disrupts the reconsolidation of these memories and reduces drinking in humans.
- Ravi K. Das
- , Grace Gale
- & Sunjeev K. Kamboj
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Article
| Open AccessAltered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets
Changes in brain structure asymmetry have been reported in autism spectrum disorder. Here the authors investigate this issue using a large-scale sample consisting of 54 data sets.
- Merel C. Postema
- , Daan van Rooij
- & Clyde Francks
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| Open AccessInternational meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.
- Caroline M. Nievergelt
- , Adam X. Maihofer
- & Karestan C. Koenen
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| Open AccessReduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging
Post-mortem studies have suggested a possible reduction in mu-opioid receptor (MOR) density in people with schizophrenia. Here, the authors examined MOR in living patients with schizophrenia using PET imaging, and found local reductions of MOR compared to controls.
- Abhishekh H. Ashok
- , Jim Myers
- & Oliver D. Howes
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| Open AccessTranscriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes
A recent GWAS reported 12 genetic loci for attention deficit/hyperactivity disorder (ADHD). Here, Liao et al. perform transcriptomic imputation using these data and 12 brain-relevant tissues from GTEx and CMC to identify 9 genes associated with ADHD by TWAS, 3 of which had not yet been reported for ADHD.
- Calwing Liao
- , Alexandre D. Laporte
- & Guy A. Rouleau
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| Open AccessLongitudinal EEG power in the first postnatal year differentiates autism outcomes
Brain oscillations may be disrupted in children with autism spectrum disorder. The authors performed a longitudinal study of electroencephalography recordings and found that EEG recordings from the first year after birth can distinguish healthy children from children with autism spectrum disorder.
- Laurel J. Gabard-Durnam
- , Carol Wilkinson
- & Charles A. Nelson
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| Open AccessCyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility
People with a genetic deletion of the 15q11.2 locus are at increased risk for psychiatric disorders and white matter disturbances, but the gene(s) responsible are unclear. Here, the authors show that low dosage of CYFIP1, present in the human 15q11.2 region, alters white matter structure and cognition in rats.
- Ana I. Silva
- , Josephine E. Haddon
- & Lawrence S. Wilkinson
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| Open AccessSphingosine-1-phosphate receptor 3 in the medial prefrontal cortex promotes stress resilience by reducing inflammatory processes
S1PR3 is a G protein coupled receptor, that has a role in inflammation. Here the authors show that in the CNS, S1PR3 may contribute to resilience to stressful experiences; resilient rodents show elevated S1pr3, and knockdown results in greater susceptibility to stress.
- Brian F. Corbett
- , Sandra Luz
- & Seema Bhatnagar
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Article
| Open AccessPaternal-age-related de novo mutations and risk for five disorders
Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.
- Jacob L. Taylor
- , Jean-Christophe P. G. Debost
- & Elise B. Robinson
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| Open AccessLocus coeruleus-CA1 projections are involved in chronic depressive stress-induced hippocampal vulnerability to transient global ischaemia
Depression and transient ischaemic attacks are tightly regulated but the neural circuits underlying depression-modulated ischaemic injury are not known. Here, the authors show that the locus coeruleus-CA1 pathway is involved in depression-associated ischaemia susceptibility.
- Qian Zhang
- , Dian Xing Hu
- & Bo Tian
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| Open AccessIndividual variability in behavior and functional networks predicts vulnerability using an animal model of PTSD
How do individual differences affect vulnerability to developing post-traumatic stress disorder (PTSD)? Here, using longitudinal testing in a rat model of PTSD, the authors show patterns of pre-trauma brain connectivity and behaviors that predict PTSD-like responses to trauma exposure.
- David Dopfel
- , Pablo D. Perez
- & Nanyin Zhang
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Article
| Open AccessLower synaptic density is associated with depression severity and network alterations
Lowered synaptic density is believed to occur in major depressive disorder and PTSD, possibly as an effect of stress. Here, the authors use positron emission tomography (PET) to measure levels of the synaptic marker SV2A and show that SV2A density is lower in those with more severe symptoms of depression.
- Sophie E. Holmes
- , Dustin Scheinost
- & Irina Esterlis
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| Open AccessDeep brain stimulation of the internal capsule enhances human cognitive control and prefrontal cortex function
Deep brain stimulation (DBS) is a promising treatment for psychiatric disorders, but its mechanism in relieving symptoms is unclear. Here, the authors show that DBS of ventral internal capsule/ventral striatum (VCVS) may act by enhancing prefrontal cortex oscillations that in turn enhance cognitive control.
- A. S. Widge
- , S. Zorowitz
- & D. D. Dougherty
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Article
| Open AccessGenome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.
- Henry R. Kranzler
- , Hang Zhou
- & Joel Gelernter
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Article
| Open AccessFunctional genomics reveal gene regulatory mechanisms underlying schizophrenia risk
We know a large number of risk SNPs for schizophrenia, but little about how these SNPs contribute to the disorder. Here, the authors use functional genomics to identify risk SNPs that disrupt transcription factor binding and validate the regulatory effects of the transcription factor binding-disrupting SNPs.
- Yongxia Huo
- , Shiwu Li
- & Xiong-Jian Luo
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| Open AccessCerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization
Brain function alterations in schizophrenia and other psychotic disorders remain poorly understood. Here, the authors discover that increased neural connectivity in the cerebello-thalamo-cortical circuitry predicts psychosis in those at high risk, and is present in people with schizophrenia.
- Hengyi Cao
- , Oliver Y. Chén
- & Tyrone D. Cannon
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| Open AccessGenome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia
Educational attainment and schizophrenia have a negative phenotypic relationship but show positive genetic correlation. Here, the authors study genetic dependence between the two traits and find that multiple genes have pleiotropic effects on both without a systematic pattern of sign concordance.
- V. Bansal
- , M. Mitjans
- & P. D. Koellinger
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| Open AccessLinked dimensions of psychopathology and connectivity in functional brain networks
Co-morbidity and symptom overlap make it difficult to associate psychiatric disorders with unique neural signatures. Here, the authors use a data-driven approach to show that the symptom dimensions of mood, psychosis, fear and externalizing behavior exhibit unique patterns of functional dysconnectivity.
- Cedric Huchuan Xia
- , Zongming Ma
- & Theodore D. Satterthwaite
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Article
| Open AccessVariations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment
Patients with schizophrenia show varied response to antipsychotics. Here, the authors demonstrate in patients under antipsychotics treatment that a haplotype associated with lower dysbindin-1 expression correlated with better executive functions, providing further mechanistic support from mouse models.
- Diego Scheggia
- , Rosa Mastrogiacomo
- & Francesco Papaleo
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Article
| Open AccessEnhanced pupillary light reflex in infancy is associated with autism diagnosis in toddlerhood
Previous studies showed that children with autism spectrum disorder (ASD) have atypicalities in the pupillary light reflex (PLR). This study uses longitudinal monitoring of infants at risk for ASD to show that PLR magnitude at 10 months of age is associated with later ASD diagnosis and symptom severity.
- Pär Nyström
- , Teodora Gliga
- & Terje Falck-Ytter
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| Open AccessGenome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways
The UK Biobank provides data for three depression-related phenotypes. Here, Howard et al. perform a genome-association study for broad depression, probable major depressive disorder (MDD) and hospital record-coded MDD in up to 322,580 UK Biobank participants which highlights excitatory synaptic pathways.
- David M. Howard
- , Mark J. Adams
- & Andrew M. McIntosh
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| Open AccessComprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes
More than 100 risk loci for schizophrenia have been identified by genome-wide association studies. Here, the authors apply an integrative genomic approach to prioritize risk genes and validate GLT8D1 and CSNK2B as candidate causal genes by in vitro studies in neural stem cells.
- Cui-Ping Yang
- , Xiaoyan Li
- & Xiong-Jian Luo
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| Open AccessTranscriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains
Induced pluripotent stem cell (hiPSC)-based models have inherent variations in their cellular and molecular output and readouts. Here, Hoffman and colleagues devise a method to account for gene expression variations in hiPSC-derived neurons from patients with childhood-onset schizophrenia.
- Gabriel E. Hoffman
- , Brigham J. Hartley
- & Kristen J. Brennand
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| Open AccessCross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder
“There have been a number of recent epigenetic studies on autism spectrum disorder. Here, the authors integrate genetic and epigenetic data from cord and peripheral blood and also from brain tissues to show the potential of blood-based epigenetic data to provide insights into psychiatric disorders.”
- Shan V. Andrews
- , Shannon E. Ellis
- & M. Daniele Fallin
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| Open AccessIntegrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.
- Hyun Ji Noh
- , Ruqi Tang
- & Kerstin Lindblad-Toh
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| Open AccessReproductive fitness and genetic risk of psychiatric disorders in the general population
Why genetic variants that confer risk for psychiatric disorders persist in the genome is an evolutionary conundrum. Here, Mullinset al. report association of polygenic risk for autism with having fewer children and polygenic risk for ADHD with higher reproductive fitness.
- Niamh Mullins
- , Andrés Ingason
- & Kari Stefansson
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Article
| Open AccessExperimental evidence for circular inference in schizophrenia
Schizophrenia is a mental disorder characterized by hallucinations and delusions. Here the authors report a novel probabilistic inference task in which compared to healthy subjects, schizophrenia patients show greater degree of circular inference that matches the severity of their clinical symptoms.
- Renaud Jardri
- , Sandrine Duverne
- & Sophie Denève
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Article
| Open AccessDe novo genic mutations among a Chinese autism spectrum disorder cohort
Recurrent sporadic mutations are important risk factors for autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, Eichler, Xia and colleagues analyse risk genes in a large Chinese ASD cohort and find novel recurrences of potential pathogenic significance.
- Tianyun Wang
- , Hui Guo
- & Evan E. Eichler
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Article
| Open AccessBrain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice
The in vivo function of CRMP2 is unclear. Zhang et al. generate and characterize brain-specific Crmp2knockout mice. These mice show impairments in hippocampal neurogenesis, neuronal maturation and synaptic transmission, and exhibit schizophrenia-related behavioral deficits.
- Hongsheng Zhang
- , Eunchai Kang
- & Zhiheng Xu
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Article
| Open AccessEmerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders
The molecular mechanisms of neurotrophin receptor trafficking are only partially understood. Here the authors show that ARHGAP33 interacts with SORT1 to regulate TrkB trafficking, the dysfunction of which impairs synapse development and leads to schizophrenia-related behavioural abnormalities in mice.
- Takanobu Nakazawa
- , Ryota Hashimoto
- & Masanobu Kano
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Article
| Open AccessAn excitatory ventral hippocampus to lateral septum circuit that suppresses feeding
The ventral hippocampus connects to the hypothalamus and has been implicated in feeding behaviours. Here, the authors use a combination of optogenetics and DREADD strategies to dissect the underlying circuit, showing that projections from the vHC to the lateral septum work to regulate feeding suppression.
- Patrick Sweeney
- & Yunlei Yang
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Article
| Open AccessLong-term neural and physiological phenotyping of a single human
Large-scale, multimodal phenotypic characterisation is a valuable tool to explore brain function. Poldrack et al. collect and relate MRI, psychological, physiological, metabolic and gene expression data from a single human over an 18 month period, providing a rich resource for future studies.
- Russell A. Poldrack
- , Timothy O. Laumann
- & Jeanette A. Mumford
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Article
| Open AccessParacingulate sulcus morphology is associated with hallucinations in the human brain
Hallucinations can occur in both healthy individuals and patients with psychiatric disorders. Garrison et al. here report that specific brain morphology differences in the paracingulate sulcus (PCS) can determine the occurrence of hallucinations in schizophrenia, irrespective of sensory modality.
- Jane R. Garrison
- , Charles Fernyhough
- & Jon S. Simons
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Article
| Open AccessGenome-wide burden of deleterious coding variants increased in schizophrenia
Schizophrenia is a complex disorder with high heritability but poorly understood genetics. Here Olde Loohuis et al.compare schizophrenia patients to unaffected individuals and identify an increased individual burden of rare deleterious mutations in patients.
- Loes M. Olde Loohuis
- , Jacob A. S. Vorstman
- & Roel A. Ophoff
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| Open AccessVentral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression
Enhanced glutamatergic transmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of depression, yet the underlying source is not known. Here, the authors demonstrate a unique role for ventral hippocampal-NAc glutamatergic projections in regulating depression-like behaviour.
- Rosemary C. Bagot
- , Eric M. Parise
- & Eric J. Nestler
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Interaction between emotional state and learning underlies mood instability
Whether emotional state affects the perception of outcomes, and the possible consequences of this interaction remain unclear. Here the authors use behavioural tests and brain imaging to study the bidirectional interaction between emotional state and learning in humans and find that this interaction may play a role in mood instability.
- Eran Eldar
- & Yael Niv
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Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour
Synthetic compounds that alter circadian rhythms have been shown to modulate energy expenditure and systemic metabolism in rodents. Here, the authors study the psychological effects of such compounds, and find synthetic REV-ERB agonists increase wakefulness and reduce anxiety-like behaviour in mice.
- Subhashis Banerjee
- , Yongjun Wang
- & Thomas P. Burris
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Article
| Open AccessTranscriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism
Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. In this study, the authors use RNA sequencing analyses to characterize differences in the transcriptome between autistic and typically developing brains.
- Simone Gupta
- , Shannon E. Ellis
- & Dan E. Arking