Resources

The hypothalamic arcuate–median eminence (Arc-ME) complex is rich with functionally distinct cell types, a fraction of which have been characterized. The authors profile 20,921 individual cells by single-cell RNA-seq, identifying 50 Arc-ME cell types and their markers, determining each's response to energy status and implicating two neuron populations in the genetic control of obesity.

Su et al. investigated the chromatin accessibility status of neurons in the adult mouse dentate gyrus at different timepoints after activation at the genome-wide level. Their study provides a potential mechanism by which neuronal activity may reshape the epigenetic landscape, thereby dynamically changing transcriptome and neuronal properties over time.

Top-down control is important for sensory processing. In this study, the authors used virus-assisted circuit mapping to identify the brain networks for top-down modulation of multiple sensory modalities and the subnetworks within the visual network, thus providing an anatomical foundation for understanding the brain mechanisms underlying top-down control of behavior.

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.

Hintiryan, Foster et al. present an online mouse cortico-striatal projectome describing projections from the entire cortex to dorsal striatum. Computational neuroanatomic analysis of these projections identified 29 distinct striatal domains. This connectomics approach was applied to characterize circuit-specific cortico-striatal connectopathies in a mouse model of Huntington disease and in monoamine oxidase (MAO) A/B knockout mice.

RNA sequences are generally considered to be a mirror of DNA sequences. However, that dogma has become challenged as RNA editing is increasingly recognized. This study explored the global landscape of RNA editing in human brain development and revealed its dynamic aspects, providing insight into epitranscriptional regulation of sequence diversity.

ALS patient iPSC-derived motor neurons aim to model disease phenotypes. The authors demonstrate that these cells transcriptomically resemble fetal rather than adult spinal motor neurons, and familial and sporadic forms of ALS disrupt gene networks and pathways associated with neuronal maturation and aging. These data provide a resource for further understanding how molecular changes in motor neurons lead to disease.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease pathogenesis, the authors profiled mRNA in over 600 brain and peripheral tissue samples from Huntington's disease knock-in mice with increasing CAG repeat lengths. Coexpression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age.

Gene-regulatory elements are drivers of evolutionary divergence, yet where these are located and which are evolutionarily relevant is unclear. In this work, large-scale epigenomic analysis of human, rhesus and chimpanzee brain tissue allowed the identification of human-specific gene-regulatory changes that contributed to the emergence of the human brain.

Heterogeneity within distinct cell populations resident in the central nervous system is increasingly recognized as important for functional diversity, plasticity and sensitivity to neurological disease. The authors demonstrate genome-wide diversity of microglia dependent on brain localization in the young adult and show that aging of microglia occurs in a regionally variable manner.

Mammalian cortex comprises a variety of cells, but the extent of this cellular diversity is unknown. The authors defined cell types in the primary visual cortex of adult mice using single-cell transcriptomics. This revealed 49 cell types, including 23 GABAergic, 19 glutamatergic and 7 non-neuronal types.

The authors applied a correlation-based metric, ‘differential stability’ (DS), to assess reproducibility of gene expression patterning across individual brains, revealing mesoscale genetic organization. The highest DS genes were enriched for brain-related biological annotations, disease associations and drug targets, and their anatomical expression pattern correlated with resting state functional connectivity.

The authors performed a comprehensive proteome analysis of the adult mouse brain, its major regions and CNS cell types at a depth of >13,000 proteins. This new resource represents the largest collection of cell type–resolved protein expression data of the brain. The power of the data set was illustrated by identifying novel adhesion molecules in glia and neuron interaction.

The authors used trans-synaptic tracing to examine and compare circuit anatomy in mouse barrel and medial prefrontal cortex, revealing novel organizational features and contrasts between the two areas. Notably, medial prefrontal layer 5 neurons receive more long-distance inputs and more local inhibitory inputs than layer 5 neurons in barrel cortex.

To elucidate novel molecular mechanisms underlying neurodegeneration in Parkinson's disease, the authors generated mice for cell type-specific profiling of dopaminergic neurons. Regulatory network analysis of translatome libraries from dopaminergic neurons under degenerative stress facilitated the identification of intrinsic upstream regulators that oppose degeneration. This strategy can be generalized to investigate degeneration of other classes of neurons.

Evidence suggests that aberrant RNA processing contributes to amyotrophic lateral sclerosis (ALS). Using RNA sequencing, Prudencio et al. assessed the extent of transcriptome defects in C9orf72-associated (c9ALS) and sporadic ALS (sALS) brains. They report extensive defects in expression, alternative splicing and alternative polyadenylation that are significantly distinct between individuals with c9ALS and sALS.

Abnormal post-translational modifications of tau may contribute to Alzheimer's disease, but normal tau modifications are poorly understood. Using advanced mass spectrometry, a great variety of modifications were identified on endogenous mouse tau. Tau appears to be highly regulated and may fulfill diverse functions, most of which remain to be defined.

Identifying enhancers regions has been primarily focused on model organisms and human transformed cell lines. This study characterizes enhancer RNA (eRNA) expression in the human brain by identifying brain region–specific eRNAs and assessing eRNA-gene coexpression interactions. The authors further demonstrate an enrichment of brain eRNAs for autism-associated genetic variants.

The authors discovered that circular RNAs are significantly enriched in the mouse brain and can be visualized in situ, near synapses. They observed that many circRNAs change their abundance during synaptogenesis and also following neuronal homeostatic plasticity, suggesting a function for circRNA in regulating synaptic development and plasticity.

Brain transcriptomics is limited by existing annotations of expressed gene products. Here the authors identify differentially expressed regions of the genome across development and aging in the human brain. These transcripts were developmentally conserved across the human and mouse and enriched for genetic variants associated with neurodevelopmental disorders.