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Gustavo Turecki and colleagues report that miR-1202, a miRNA specific to primates, is decreased in individuals with depression and seems to be differentially regulated in individuals who will end up showing beneficial responses to antidepressant treatment compared to those who will not respond.

Suicide is one of the leading causes of death for people of all ages in the developed world and is associated with various risk factors. Here, Gustavo Turecki reviews the molecular processes that may predispose individuals to suicide, mediate suicidal ideation and behaviour, and trigger suicidal events.

Sex differences in brain transcriptomics have unknown cell type specificity. Here, authors show concordant cortical transcriptomic patterns in depression within individual cell types between sexes, but distinctly affected top cell types and genes.

It is not fully understood why some patients respond or do not respond to antidepressant treatment. Here the authors show that in the blood of individuals with depression, GPR56 expression increases in responders to antidepressant treatment, but not in non-responders.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

The mechanisms of neurovascular adaptations underlying stress resilience remain unclear. Here the authors show that the astrocytic endocannabinoid system modulates the blood–brain barrier changes during stress in adult mice.

Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.

Childhood abuse or neglect alters the hormonal stress response and increases the risk for suicide. Analysis of hippocampal samples from human suicide victims with a history of child abuse indicated changes in the expression of the NC3R1 gene that did not occur in suicide victims with no childhood abuse or in people who died of other causes.

Antidepressant drugs are the most common treatment for depressive episodes but only a fraction of patients experience adequate response. Here the authors find dysregulation of miRNAs in peripheral blood samples from depressed patients after antidepressant treatment, and show that the miRNAs are regulators of psychiatrically relevant signalling pathways.

For allele-specific expression and RNA editing studies, targeted RNA sequencing using microfluidic multiplexed PCR (mmPCR-seq) gives robust high-throughput measurements of allelic ratios across the dynamic range of gene expression, even for low-quantity or low-quality RNA.

Juliane Winkelmann and colleagues report that two common variants in the 5′ UTR of PTPRD are independently associated with restless legs syndrome. PTPRD encodes a receptor-like protein tyrosine phosphatase previously implicated in axon guidance and motor neuron development.

Recent research sheds light on sex-specific molecular changes in the brains of MDD patients, but their association with specific symptoms is still uncertain. Here, the authors revealed the existence of gene signatures underlying the expression of distinct symptom domains in the brain of men and women with depression.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

The vascular, cellular and molecular changes underlying sex differences in mood disorders are unclear. Here, the authors show that blood-brain barrier dysfunction modulates anxiety- and depressive-like behaviors in female mice and endothelium-specific changes associated with maladaptive responses compared to resilience to stress.

Single-nucleus transcriptomics reveal brain alterations associated with major depression. Deep layer excitatory cells and immature oligodendrocytes showed most changes, involving synaptic plasticity, immune function and steroid hormones.

The cellular and molecular mechanisms underlying major depressive disorder are unclear. Here, the authors report cell type- and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behavior in female non-human primates.

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.

Researchers identify a transcriptional network engaged in stress-resilient mice that is regulated by a previously unstudied transcription factor, Zfp189, and elucidate molecular mechanisms controlling this network and resilience behavior.

A single-cell transcriptomic atlas from embryonal pons and forebrain provides insights into the developmental origins of pediatric brain tumors. The study identifies impaired differentiation of specific neural progenitors as a common mechanism underlying these cancers.

Bipolar disorder (BD) is a severe mood disorder, which has been shown to have a large genetic component. Here the authors identify two previously unreported BD risk loci and provide further insights into the biological mechanisms underlying BD development.

Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.

There are widespread genetic effects on DNA methylation in the developing brain. Fetal brain mQTLs are enriched in regulatory domains, overlapping with variants influencing gene expression. Most are developmentally stable, but some are fetal specific. These mQTLs are enriched in genomic regions associated with schizophrenia, a neuropsychiatric disorder with neurodevelopmental origins.

Translation of mRNA contributes to neuronal function and complex behaviours, and inflammation is thought to contribute to depression. Here the authors show that mice lacking phosphorylation sites in eIF4E (eukaryotic initiation factor 4E) display anxiety- and depression-like behaviour and decreased IkBα expression; furthermore TNFα delivery to the medial prefrontal cortex induces depression-like behaviour and deficits in serotonergic transmission.

Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.

Suicide and suicidal behaviour continue to present key challenges for public policy and health services. This Primer discusses the global burden of suicide and suicidal behaviours, and provides an overview of our current understanding of the mechanisms of suicide, including risk factors for suicidal ideation and the transition from ideation to suicide attempt.

Changes in brain gene expression by cocaine are known to involve epigenetic machineries. The histone methyltransferase G9a is a mediator of cocaine-induced structural and behavioral plasticity in the nucleus accumbens of mouse. This study finds cocaine-induced, G9a-mediated gene repression in both direct and indirect pathway medium spiny neurons (MSNs). The study also uses cell type–specific overexpression and conditional knockout of G9a in each MSN cell type and shows that G9a influences the developmental specification of striatal MSN subtypes, which in turn affects behavioral response to cocaine.

Upregulation of the ATP-dependent ACF chromatin-remodeling complex in the NAc is a necessary and causal component for susceptibility to stress-induced depressive behaviors in mice, and this complex is also shown to be upregulated in the NAc of depressed humans.

Chronic stress and depression induce structural and functional plasticity; however, the mechanisms responsible for these alterations remain incompletely characterized. Here Scott J Russo and colleagues demonstrate that the Rac1 promoter is epigenetically modified, and its expression is reduced in the nucleus accumbens of mice after chronic defeat stress and in subjects with major depressive disorders. Reduced Rac1 expression is sufficient to induce depression-related behavior and stubby spine formation in mice.

Expression of TET1 dioxygenase, which catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, is downregulated by repeated cocaine administration in mouse nucleus accumbens, where it controls cocaine reward. Genome-wide mapping of 5-hydroxymethylcytosine in this brain region reveals novel modes of epigenetic regulation by cocaine.

The authors describe an optimized workflow for isolating single nuclei from archived postmortem tissues that does not require sorting or ultracentrifugation and can be used in snRNA and ATAC sequencing pipelines.