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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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?
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.
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.
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.
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.
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.
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.
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.
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.
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.