Focus 26 October 2016

Psychiatric Disorders

Compared to other areas in medicine, psychiatric research faces unique biological, technological, clinical, regulatory and ethical challenges. In this joint focus Nature Neuroscience and Nature Medicine provide a collection of Commentaries, Perspectives, and Reviews from leaders in the field that address these challenges and provide an authoritative overview of basic and clinical sciences advancing mental health research.

As always, Nature Neuroscience and Nature Medicine retain sole responsibility for all editorial content.

Content

Focus on psychiatric disorders

Nature Neuroscience presents a Focus issue highlighting progress in basic and clinical sciences advancing mental health research.

Editorial26 Oct 2016 Nature Neuroscience
Mental health horizons

From organoids to population-level studies, mental health research has begun to crack long-standing mysteries. Longitudinal investigations into brain and cognitive development among adolescents, such as the forthcoming 10,000-person ABCD project, will help to mature the field.

Editorial8 Nov 2016 Nature Medicine
Back to basics: luring industry back into neuroscience

An obsession with producing and validating models (face, construct, predictive validity) has led many of us down a deep rabbit hole, thinking about models instead of mechanisms. Advances in the human genetics and neurobiology of brain disorders create exciting new opportunities, but only if we can get back to basics.
- Steven E Hyman
Correspondence26 Oct 2016 Nature Neuroscience
On being a circuit psychiatrist

Recent technological advancements in the study of neural circuits provide reasons to be optimistic that novel treatments for psychiatric illnesses are just around the corner. Maximizing the chances of translating these advancements into real improvements in patient care requires a carefully considered road map.
- Joshua A Gordon
Commentary26 Oct 2016 Nature Neuroscience
Psychiatric distress in animals versus animal models of psychiatric distress

Primatology research suggests that other primates suffer from crippling depression or anxiety, implying that these diseases' roots pre-date human history. At the same time, some realms of psychiatry remain uniquely human. Recognizing the similarities and dissimilarities between us and other primates is essential in studying animal models of psychiatric disease.
- Robert M Sapolsky
Commentary26 Oct 2016 Nature Neuroscience
The origin and natural history of autism spectrum disorders

Refined social phenotyping of syndromic and idiopathic forms of autism, combined with advances in genetics, animal models of syndromes and brain imaging, may facilitate discovery of shared brain mechanisms that will lead to new treatments. The reversal of social deficits in animal models is promising for eventual translation into therapeutics.
- James C Harris
Commentary26 Oct 2016 Nature Neuroscience
Translating genome-wide association findings into new therapeutics for psychiatry

The Psychiatric Genomics Consortium is aiming to analyze data from >1 million individuals. This is already leading to hundreds of new genetic findings across psychiatric disorders with the potential to restart largely stalled psychiatric drug development pipelines. This paper outlines key questions and plans to translate findings into new therapeutics.
- Gerome Breen
- Qingqin Li
- Howard J Edenberg
Commentary26 Oct 2016 Nature Neuroscience
The implications of the shared genetics of psychiatric disorders

Recent studies have led to the identification of genetic loci that are shared between psychiatric disorders. Here O’Donovan and Owen argue that it is unlikely that risk alleles exist that are singular to any one such disorder.
- Michael C O'Donovan
- Michael J Owen
Perspective26 Oct 2016 Nature Medicine
Developmental timing and critical windows for the treatment of psychiatric disorders

The developmental trajectories of neuropsychiatric disorders suggest that early life events might contribute substantially to disease. Here the author discusses the potential to treat within these critical time windows of development to alter disease course.
- Oscar Marín
Perspective26 Oct 2016 Nature Medicine
The promises and challenges of human brain organoids as models of neuropsychiatric disease

Psychiatric disorders are difficult to model owing to their inherent complexity and heterogeneity. This Perspective focuses on the use of 3D brain organoids in modeling these disorders, considering both their advantages and their limitations.
- Giorgia Quadrato
- Juliana Brown
- Paola Arlotta
Perspective26 Oct 2016 Nature Medicine
Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis

Recent evidence indicates that one of the underlying mechanisms in the pathogenesis of neuropsychiatric disorders is dysregulated dentate gyrus neurogenesis. Here the authors present evidence supporting this hypothesis and suggest therapeutic avenues.
- Sanghee Yun
- Ryan P Reynolds
- Amelia J Eisch
Perspective26 Oct 2016 Nature Medicine
The search for imaging biomarkers in psychiatric disorders

Abi-Dargham and Horga discuss the challenges of developing and standardizing brain-imaging technologies to aid with the diagnosis and treatment of psychiatric disorders.
- Anissa Abi-Dargham
- Guillermo Horga
Perspective26 Oct 2016 Nature Medicine
The road to precision psychiatry: translating genetics into disease mechanisms

Recently, robust identification of hundreds of genetic variants associated with risk for neuropsychiatric disease has prompted new challenges in understanding their biological impact within an individual. The authors provide a framework for interpretation of genetic risk variants to uncover disease mechanisms and facilitate therapeutic development.
- Michael J Gandal
- Virpi Leppa
- Daniel H Geschwind
Review Article26 Oct 2016 Nature Neuroscience
Lessons learned from studying syndromic autism spectrum disorders

Autism spectrum disorders are highly heterogeneous and include both idiopathic and syndromic forms. Sztainberg and Zoghbi discuss insights gained from studying syndromic autism spectrum disorders and their potential contribution to our understanding of the molecular pathways critical for normal cognitive and social development, as well as the relevance to idiopathic autism.
- Yehezkel Sztainberg
- Huda Y Zoghbi
Review Article26 Oct 2016 Nature Neuroscience
Using model systems to understand errant plasticity mechanisms in psychiatric disorders

Animal models have failed to yield new treatments for psychiatric disorders. Some psychiatric disorders may result from pathology in plasticity mechanisms. Therefore, understanding plasticity mechanisms in model systems may provide insight into the disordered processes in patients.
- Bruno B Averbeck
- Matthew V Chafee
Review Article26 Oct 2016 Nature Neuroscience
Rare variants are common in schizophrenia

A large DNA sequencing study of schizophrenia finds more evidence that rare inherited coding mutations across many genes contribute to risk of the disorder. This has important implications for geneticists and neuroscientists alike.
- Jacob Gratten
News & Views26 Oct 2016 Nature Neuroscience
Brains, genes and power

Gene expression data from more than 500 human brains shed light on the molecular consequences of genetic variation that contributes to schizophrenia.
- Frank W Albert
News & Views26 Oct 2016 Nature Neuroscience
When size matters: CHD8 in autism

Recent models studying loss of the mouse homolog of the autism-associated gene CHD8 show altered Wnt signaling, cell fate and proliferation. How do these findings shape our understanding of this disease?
- Martin W Breuss
- Joseph G Gleeson
News & Views26 Oct 2016 Nature Neuroscience
Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

Using whole-exome sequencing, the authors identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) and found that gene-disruptive and putatively protein-damaging URVs were significantly more abundant in schizophrenia cases than in controls. The excess of protein-compromising URVs was concentrated in brain-specific genes, particularly in neuronally expressed genes whose proteins are located at the synapse.
- Giulio Genovese
- Menachem Fromer
- Steven A McCarroll
Article3 Oct 2016 Nature Neuroscience
Gene expression elucidates functional impact of polygenic risk for schizophrenia

The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of subjects with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, they found that ∼20% of schizophrenia loci have variants that may contribute to altered gene expression and liability.
- Menachem Fromer
- Panos Roussos
- Pamela Sklar
Article26 Sep 2016 Nature Neuroscience
Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder

Autism spectrum disorder is a complex disease with a strong genetic basis that remains under-characterized by current genetics studies. Here, the authors use a computational approach based on a human brain-specific gene network to predict autism-associated genes across the genome and further delineate their functional and developmental characteristics.
- Arjun Krishnan
- Ran Zhang
- Olga G Troyanskaya
Article1 Aug 2016 Nature Neuroscience
Genome-wide, integrative analysis implicates microRNA dysregulation in autism spectrum disorder

The authors performed genome-wide microRNA (miRNA) expression profiling in post-mortem brains from individuals with autism spectrum disorder (ASD) and controls, and identified miRNAs and co-regulated modules perturbed in ASD.
- Ye E Wu
- Neelroop N Parikshak
- Daniel H Geschwind
Article29 Aug 2016 Nature Neuroscience
Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling

De novo mutations in CHD8 are associated with autism spectrum disorder, but the basic biology of CHD8 remains poorly understood. Here the authors find that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice.
- Omer Durak
- Fan Gao
- Li-Huei Tsai
Article3 Oct 2016 Nature Neuroscience
Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics

Social encounters are associated with varying degrees of stress. The authors show that modulation of stress system components in the medial amygdala alters preference for familiar vs. novel conspecifics. Inhibition of the relevant circuit in a group of familiar mice kept under semi-natural conditions increased pro-social behavior.
- Yair Shemesh
- Oren Forkosh
- Alon Chen
Article18 Jul 2016 Nature Neuroscience
Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

Mutations in MECP2 cause Rett syndrome. The authors show that a MeCP2-HDAC3 complex positively regulates a subset of neuronal genes through FOXO recruitment and deacetylation, and that HDAC3 loss contributes to cognitive and social deficits in mice. Rett-patient-derived cells exhibited similar HDAC3-FOXO-mediated transcriptional impairments and were rescued by gene editing.
- Alexi Nott
- Jemmie Cheng
- Li-Huei Tsai
Article18 Jul 2016 Nature Neuroscience
MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors

Loss of Hdac1 and Hdac2 in adult brain is detrimental to neuronal survival and triggers dysregulation of Sapap3 in the striatum in a MeCP2-dependent manner that results in an exacerbated repetitive behavior phenotype.
- Melissa Mahgoub
- Megumi Adachi
- Lisa M Monteggia
Article26 Sep 2016 Nature Neuroscience
Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c

Chen et al. found that Foxp2 interacts with Mef2c to wire synaptic circuits linking neocortex to basal ganglia. The study analyzes the basics of circuit wiring underlying vocal communication.
- Yi-Chuan Chen
- Hsiao-Ying Kuo
- Fu-Chin Liu
Article5 Sep 2016 Nature Neuroscience
Multimodal population brain imaging in the UK Biobank prospective epidemiological study

The UK Biobank combines detailed phenotyping and genotyping with tracking of long-term health outcomes in a large cohort. This study describes the recently launched brain-imaging component that will ultimately scan 100,000 individuals. Results from the first 5,000 subjects are reported, including thousands of associations, population modes and hypothesis-driven results.
- Karla L Miller
- Fidel Alfaro-Almagro
- Stephen M Smith
Resource19 Sep 2016 Nature Neuroscience

Psychiatric Disorders

Content

Focus on psychiatric disorders

Mental health horizons

Back to basics: luring industry back into neuroscience

On being a circuit psychiatrist

Psychiatric distress in animals versus animal models of psychiatric distress

The origin and natural history of autism spectrum disorders

Translating genome-wide association findings into new therapeutics for psychiatry

The implications of the shared genetics of psychiatric disorders

Developmental timing and critical windows for the treatment of psychiatric disorders

The promises and challenges of human brain organoids as models of neuropsychiatric disease

Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis

The search for imaging biomarkers in psychiatric disorders

The road to precision psychiatry: translating genetics into disease mechanisms

Lessons learned from studying syndromic autism spectrum disorders

Using model systems to understand errant plasticity mechanisms in psychiatric disorders

Rare variants are common in schizophrenia

Brains, genes and power

When size matters: CHD8 in autism

Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

Gene expression elucidates functional impact of polygenic risk for schizophrenia

Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder

Genome-wide, integrative analysis implicates microRNA dysregulation in autism spectrum disorder

Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling

Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics

Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors

Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c

Multimodal population brain imaging in the UK Biobank prospective epidemiological study

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