Biology subjects

Ament, S. A.

Publications and source records attributed to Ament, S. A..

At least 19 recordsLinked to original sources

bioRxiv2026

A consensus atlas of human brain development defines cell type-specific maturation trajectories across the lifespan

Human neurodevelopment is a continuous process that begins prenatally and extends into postnatal life. Current transcriptomic datasets are limited, fragmented across analytical frameworks, precluding comprehensive reconstruction of cellular trajectories linking developmental states to mature cell types. Here we present a consolidated cellular-resolution transcriptomic atlas of human brain development from the onset of neurogenesis to adulthood, covering [~]2.2 million cells from 156 donors across nine studies. All data were reprocessed from raw sequencing reads and annotated within a unified cell-type taxonomy, enabling reliable mapping across the lifespan. Cell types were highly replicable across heterogeneous datasets, enabling us to chart their maturation and cortical layer localization over time. We identify dynamic gene programs predictive of cell-type maturation, validate gene modules tracking known fate transitions, and leverage our atlas scale to characterize rare populations, including microglia. This resource establishes a standardized reference of human brain development and maturation gene modules for future comparisons across model systems, species, and disease states.

neuroscience↗

bioRxiv2026

Molecular adaptations of activated T-cells in an inflammation-associated schizophrenia sub-group

Thirty-five percent of people with schizophrenia-related disorders (SRD) form a high-inflammation subgroup defined by elevated anti-gliadin antibodies (AGA+) and inflammatory proteins and associated with an increased severity of negative symptoms. However, the immune mechanisms mediating these effects remain poorly defined. Here, we characterized transcriptional signatures of peripheral immune cells in AGA+ SRD (n=7) compared to AGA-negative (AGA-) SRD (n=3) and healthy controls (HC; n=5), using single-cell RNA-sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs). AGA+ SRD was associated with increased abundance of T-helper-17 cells (Th17), T-follicular helper-1 (Tfh1), CD5+ B cells, plasmacytoid dendritic cells (pDCs), and several CD8+ T cell subsets, including memory and Natural Killer-T-like activated subsets. In parallel, AGA-SRD exhibited a higher abundance of several monocyte subsets compared to either AGA+ SRD or HC. Pathway analysis revealed upregulation in AGA+ SRD of JAK/STAT, type I Interferon, and IL-6 signaling pathways in distinct subset of activated T-cells. Collectively, these results define a unique T cell predominant inflammatory signature in AGA+ SRD, as well as potential targets for therapeutic intervention.

genomics↗

bioRxiv2026

pertTF: context-aware AI modeling for genome-scale and cross-system perturbation prediction

Predicting genetic perturbation responses at a single-cell level is central to building models for cell state and disease. However, existing approaches are limited on predicting phenotypic outcomes beyond expression changes and generalizing predictions across genome-scale perturbations in biologically relevant contexts. Here we introduce pertTF, a transformer-based single-cell genetic perturbation model. pertTF was trained from a unique dataset capturing single cell expressions profiles of 30 full gene knockouts across 14 relevant cell types during human pancreatic development and beta-cell differentiation. pertTF outperforms current methods in predicting expression changes of perturbing unseen genes in unseen cellular contexts. In addition, pertTF infers perturbation-induced shifts in cell identity and population composition, an important phenotypic outcome of perturbation in many physiology and disease settings. Through transfer learning, pertTF operates in physiologically relevant systems, including primary human islets, where large-scale perturbation experiments are challenging. The generalizability of pertTF is further demonstrated by in silico pooled and single-cell CRISPR screens, capturing critical regulators of stem cells and early pancreatic cell development. These results establish pertTF as a framework for integrating large-scale single-cell perturbation data with AI models to predict genetic perturbation effects across cellular systems and disease contexts.

bioinformatics↗

bioRxiv2025

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

neuroscience↗

bioRxiv2025

Single-nucleus RNA sequencing reveals the cellular diversity of cerebrospinal fluid in the context of intraventricular hemorrhage

BackgroundIntraventricular hemorrhage (IVH) is a common and severe complication of hemorrhagic brain injury. Current treatments offer limited improvement in long-term neurological outcomes. Inflammatory responses in the cerebrospinal fluid (CSF) after IVH are thought to drive secondary injury, but the cellular mechanisms underlying this inflammation remain poorly defined. MethodsWe performed single-nucleus RNA sequencing of leukocytes isolated from CSF collected through external ventricular drains in subjects with intracerebral (n = 6) or subarachnoid (n = 1) hemorrhage. We characterized transcriptionally distinct subpopulations of neutrophils, monocytes, and lymphocytes by comparison to reference datasets. Cell-cell signaling networks were analyzed to infer cytokine-mediated communication, and a flow cytometry panel was developed to validate transcriptomic findings in independent CSF samples. ResultsWe obtained 11,191 high-quality nuclei comprising neutrophils (53.8%), monocytes (26.1%), lymphocytes (17.8%), and non-immune cells (2.4%). Neutrophils segregated into Nascent, Quiescent, and Interferon-Activated states. Monocytes exhibited classical phenotypes that include interferon-activated states (characterized by expression of VCAN or PROK2) and CXC-chemokine expressing states (characterized by expression of CXCL5 or CXCL8). Lymphocytes were mainly naive and central memory CD4 T cells. Cell-cell signaling analysis predicted strong CXC chemokine signaling from monocytes to neutrophil subsets and IL-1 family-driven inflammatory responses across multiple populations. Type I and III interferon signaling defined a neutrophil population not previously described in the central nervous system. ConclusionThis study delineates the diverse cellular immune landscape of CSF after IVH. Transcriptomic profiles reveal interferon, IL-1, and CXC chemokine signaling networks as potential therapeutic targets to mitigate secondary injury.

genomics↗

bioRxiv2025

Nucleus accumbens neuron subtype translatome signatures in socially stress females

Major depressive disorder (MDD) disproportionately affects women, yet the molecular mechanisms underlying female vulnerability remain poorly understood. The nucleus accumbens (NAc), a reward circuitry hub, is central to stress- and depression-related pathology. While NAc medium spiny neuron (MSN) transcriptional adaptations have been characterized in stressed male rodents, much less is known about female adaptations. To address this, we exposed female D1-Cre-RiboTag and A2A-Cre-RiboTag mice to chronic witness defeat stress (CWDS) and classified them as high- or low-social interactors. Ribosome-associated mRNA was isolated from MSN subtypes and analyzed by RNA sequencing, differential gene expression analysis (DEG), and weighted gene co-expression network analysis (WGCNA). Cross-species consensus WGCNA with male mouse and human transcriptomic datasets was performed to identify conserved, sex-specific signatures. We detected 9 differentially expressed genes (DEGs) in D1-MSNs and 630 in A2A-MSNs (FDR < 0.05). In D1-MSNs, DEGs were primarily upregulated in low interactors and enriched for energy homeostasis and cell adhesion. A2A-MSN DEGs included upregulated structural genes and downregulated neurotransmission-related genes. WGCNA identified 9 significant D1- and 5 significant A2A-MSN modules, with the most impacted enriched for PI3K-Akt-mTOR signaling and regulated by Nf1. Consensus analysis revealed a stress-associated, sex- and subtype-specific module enriched for PI3K-Akt-mTOR signaling conserved across mice and humans. These findings reveal female-specific MSN transcriptional adaptations to chronic social stress and implicate PI3K-Akt-mTOR signaling as a convergent molecular pathway. By highlighting MSN subtype-specific vulnerabilities, this work suggests potential therapeutic targets for alleviating stress-induced pathology in women with MDD.

neuroscience↗

bioRxiv2024

The transcriptome of playfulness is sex-biased in the juvenile rat medial amygdala: a role for inhibitory neurons

Social play is a dynamic behavior known to be sexually differentiated; in most species, males play more than females, a sex difference driven in large part by the medial amygdala (MeA). Despite the well-conserved nature of this sex difference and the importance of social play for appropriate maturation of brain and behavior, the full mechanism establishing the sex bias in play is unknown. Here, we explore "the transcriptome of playfulness" in the juvenile rat MeA, assessing differences in gene expression between high- and low-playing animals of both sexes via bulk RNA-sequencing. Using weighted gene co-expression network analysis (WGCNA) to identify gene modules combined with analysis of differentially expressed genes (DEGs), we demonstrate that the transcriptomic profile in the juvenile rat MeA associated with playfulness is largely distinct in males compared to females. Of the 13 play-associated WGCNA networks identified, only two were associated with play in both sexes, and very few DEGs associated with playfulness were shared between males and females. Data from our parallel single-cell RNA-sequencing experiments using amygdala samples from newborn male and female rats suggests that inhibitory neurons drive this sex difference, as the majority of sex-biased DEGs in the neonatal amygdala are enriched within this population. Supporting this notion, we demonstrate that inhibitory neurons comprise the majority of play-active cells in the juvenile MeA, with males having a greater number of play-active cells than females, of which a larger proportion are GABAergic. Through integrative bioinformatic analyses, we further explore the expression, function, and cell-type specificity of key play-associated modules and the regulator "hub genes" predicted to drive them, providing valuable insight into the sex-biased mechanisms underlying this fundamental social behavior.

neuroscience↗

bioRxiv2024

in silico transcriptome dissection of neocortical excitatory neurogenesis via joint matrix decomposition and transfer learning

Vast quantities of multi-omic data have been produced to characterize the development and diversity of cell types in the cerebral cortex of humans and other mammals. To more fully harness the collective discovery potential of these data, we have assembled gene-level transcriptomic data from 188 published studies of neocortical development, including the transcriptomes of [~]30 million single-cells, extensive spatial transcriptomic experiments and RNA sequencing of sorted cells and bulk tissues: nemoanalytics.org/landing/neocortex. Applying joint matrix decomposition (SJD) to mouse, macaque and human data in this collection, we defined transcriptome dynamics that are conserved across mammalian neurogenesis and which elucidate the evolution of outer, or basal, radial glial cells. Decomposition of adult human neocortical data identified layer-specific signatures in mature neurons and, in combination with transfer learning methods in NeMO Analytics, enabled the charting of their early developmental emergence and protracted maturation across years of postnatal life. Interrogation of data from cerebral organoids demonstrated that while broad molecular elements of in vivo development are recapitulated in vitro, many layer-specific transcriptomic programs in neuronal maturation are absent. We invite computational biologists and cell biologists without coding expertise to use NeMO Analytics in their research and to fuel it with emerging data (carlocolantuoni.org).

neuroscience↗

bioRxiv2023

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse, however it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5 {micro}g/kg/infusion) or saline for 10 days. After 24 hr abstinence, VTA nuclei were isolated and prepared for sequencing on the 10X platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signaling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signaling. In glutamate neurons, we found enrichment of genes involved in cholinergic signaling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulation of transcriptional repressor Bcl6, and upregulation of Wnt signaling partner Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signaling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA, that serves for the foundation for future mechanistic studies.

neuroscience↗

bioRxiv2022

Sex-specific transcriptomic profiling of reward and sensory brain areas in perinatal fentanyl exposed juvenile mice

Use of the synthetic opioid fentanyl increased [~]300% in the last decade, including among women of reproductive ages. Adverse neonatal outcomes and long-term behavioral disruptions are associated with perinatal opioid exposure. Our previous work demonstrated that perinatal fentanyl exposed mice displayed enhanced negative affect and somatosensory circuit and behavioral disruptions during adolescence. However, little is known about molecular adaptations across brain regions that underlie these outcomes. We performed RNA-sequencing across three reward and two sensory brain areas to study transcriptional programs in perinatal fentanyl exposed juvenile mice. Pregnant dams received 10g/ml fentanyl in the drinking water from embryonic day 0 (E0) through gestational periods until weaning at postnatal day 21 (P21). RNA was extracted from nucleus accumbens (NAc), prelimbic cortex (PrL), ventral tegmental area (VTA), somatosensory cortex (S1) and ventrobasal thalamus (VBT) from perinatal fentanyl exposed mice of both sexes at P35. RNA-sequencing was performed, followed by analysis of differentially expressed genes (DEGs) and gene co-expression networks. Transcriptome analysis revealed DEGs and gene modules significantly associated with exposure to perinatal fentanyl in a sex-wise manner. The VTA had the most DEGs, while robust gene enrichment occurred in NAc. Genes enriched in mitochondrial respiration were pronounced in NAc and VTA of perinatal fentanyl exposed males, extracellular matrix (ECM) and neuronal migration enrichment were pronounced in NAc and VTA of perinatal fentanyl exposed males, while genes associated with vesicular cycling and synaptic signaling were markedly altered in NAc of perinatal fentanyl exposed female mice. In sensory areas from perinatal fentanyl exposed females, we found alterations in mitochondrial respiration, synaptic and ciliary organization processes. Our findings demonstrate distinct transcriptomes across reward and sensory brain regions, with some showing discordance between sexes. These transcriptome adaptations may underlie structural, functional, and behavioral changes observed in perinatal fentanyl exposed mice.

neuroscience↗

bioRxiv2022

The Neuroscience Multi-Omic Archive: A BRAIN Initiative resource for single-cell transcriptomic and epigenomic data from the mammalian brain

Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org). KEY POINTSO_LIThe Neuroscience Multi-Omic Archive serves as the genomics data repository for the BRAIN Initiative. C_LIO_LIGenomic data from >50 million cells span all the major regions of the brains of humans and mice. C_LIO_LIWe provide a searchable web portal, a cloud-computing interface, and a data visualization platform. C_LI

genomics↗

bioRxiv2022

Early-childhood inflammation blunts the transcriptional maturation of cerebellar neurons

Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to risk of neurodevelopmental disorders. Here, using single-cell genomics, we characterize the postnatal development of cerebellar neurons and glia in 1-5-year-old children, comparing those who died while experiencing inflammation vs. non-inflamed controls. Our analyses reveal that inflammation and postnatal maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these brains revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those subjects experiencing inflammation. Maturation- and inflammation-associated genes were strongly enriched for those implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that the effects of inflammation correspond to blunted cellular maturation. One Sentence SummaryPost-mortem cerebelli from children who perished under conditions that included inflammation exhibit transcriptomic changes consistent with blunted maturation of Purkinje neurons compared to those who succumbed to sudden accidental death.

genomics↗

bioRxiv2022

Negative emotional behavior during fentanyl abstinence is mediated by adaptations in nucleus accumbens neuron subtypes

Opioid discontinuation generates a withdrawal syndrome marked by a negative emotional state. Increased anxiety and dysphoria during opioid discontinuation are a significant barrier to achieving long-term abstinence in opioid-dependent individuals. Adaptations in brain-reward circuitry are implicated in the opioid abstinence syndrome, but current knowledge is limited to changes following natural and semi-synthetic opioids. Here we report abstinence from the synthetic opioid fentanyl engenders structural, functional, and molecular plasticity in nucleus accumbens neuron subtypes (MSNs) that mediate negative emotional behaviors. We show fentanyl abstinence causes dendritic atrophy and increased excitatory drive exclusive to D1-receptor containing MSNs. Using subtype specific RNAseq and Weighted Gene Co-Expression Network Analysis, we identified molecular signatures of fentanyl abstinence in MSN subtypes. We found a network of co-expressed genes downregulated selectively in D1-MSNs, and transcriptionally co-regulated by E2F1. We show targeting abstinence-induced molecular changes protects D1-MSNs from maladaptive plasticity and alleviates negative emotional behaviors after fentanyl abstinence.

neuroscience↗

bioRxiv2021

Activation of Npas1-neurons in the Ventral Pallidum Mediates Stress Susceptibility

AbstractAltered activity of the ventral pallidum (VP) underlies disrupted motivation in stress and drug exposure. The VP is a very heterogeneous structure comprised of many neuron types with distinct physiological properties and projections. Neuronal PAS 1-positive (Npas1+) VP neurons are thought to send projections to brain regions critical for motivational behavior. While Npas1+ neurons have been characterized in the globus pallidus external, there is limited information on these neurons in the VP. To address this limitation, we evaluated the projection targets of the VP Npas1+ neurons and performed RNA-seq on ribosome-associated mRNA from VP Npas1+ neurons to determine their molecular identity. Finally, we used a chemogenetic approach to manipulate VP Npas1+ neurons during social defeat stress (SDS) and behavioral tasks related to anxiety and motivation in Npas1-Cre mice. We employed a similar approach in females using the chronic witness defeat stress (CWDS). We identified VP Npas1+ projections to the nucleus accumbens, ventral tegmental area, medial and lateral habenula, lateral hypothalamus, thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas1+ neurons displayed distinct transcriptomes representing distinct biological processes. Chemogenetic activation of VP Npas1+ neurons increased susceptibility to a subthreshold (S)SDS and anxiety-like behavior in the elevated plus maze and open field while the inhibition of VP Npas1+ neurons enhanced resilience to chronic (C)SDS and CWDS. Thus, the activity of VP Npas1+ neurons modulates susceptibility to social stressors and anxiety-like behavior. Our studies provide new information into VP Npas1+ neuron circuitry, molecular identity, and their role in stress response.

neuroscience↗

bioRxiv2021

Cochlear organoids reveal epigenetic and transcriptional programs of postnatal hair cell differentiation from supporting cells

We explored the transcriptional and epigenetic programs underlying the differentiation of hair cells from postnatal progenitor cells in cochlear organoids. Heterogeneity in the cells including cells with the transcriptional signatures of mature hair cells allowed a full picture of possible cell fates. Construction of trajectories identified Lgr5+ cells as progenitors for hair cells and the genomic data revealed gene regulatory networks leading to hair cells. We validated these networks, demonstrating dynamic changes both in expression and predicted binding sites of these transcription factors during organoid differentiation. We identified known regulators of hair cell development, Atoh1, Pou4f3, and Gfi1, and predicted novel regulatory factors, Tcf4, an E-protein and heterodimerization partner of Atoh1, and Ddit3, a CCAAT/enhancer-binding protein (C/EBP) that represses Hes1 and activates transcription of Wnt signaling-related genes. Deciphering the signals for hair cell regeneration from mammalian cochlear supporting cells reveals candidates for HC regeneration which is limited in the adult.

developmental biology↗

bioRxiv2021

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the prenatal human hypothalamus

The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. We sequenced the transcriptomes of 40,927 cells from the prenatal human hypothalamus spanning from 6 to 25 gestational weeks and 25,424 mature neurons in regions of the adult human hypothalamus, revealing a temporal trajectory from proliferative stem cell populations to mature neurons and glia. Developing hypothalamic neurons followed branching trajectories leading to 170 transcriptionally distinct neuronal subtypes in ten hypothalamic nuclei in the adult. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence from the same individuals, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. Cross-species comparisons to the mouse hypothalamus identified human-specific POMC populations expressing unique combinations of transcription factors and neuropeptides. These results provide the first comprehensive transcriptomic view of human hypothalamus development at cellular resolution. One-Sentence SummaryUsing single-cell genomics, we reconstructed the developmental lineages by which precursor populations give rise to 170 distinct neuronal subtypes in the human hypothalamus.

neuroscience↗

bioRxiv2021

Regulome-wide association study identifies enhancer properties associated with risk for schizophrenia

Genetic risk for complex traits is strongly enriched in non-coding genomic regions involved in gene regulation, especially enhancers. However, we lack adequate tools to connect the characteristics of these disruptions to genetic risk. Here, we propose RWAS (Regulome Wide Association Study), a new framework to identify the characteristics of enhancers that contribute to genetic risk for disease. Applying our technique to interrogate genetic risk for schizophrenia, we found that risk-associated enhancers in this disease are predominantly active in the brain, evolutionarily conserved, and AT-rich. The association between AT percentage and risk corresponds to an overrepresentation in risk-associated enhancers for the binding sites of transcription factors that recognize AT-rich cis-regulatory motifs. Several of the TFs identified in our model as being overrepresented in risk-associated enhancers, including MEF2C, are master regulators of neuronal development. The genes that encode several of these TFs are themselves located at genetic risk loci for schizophrenia. This list also includes brain-expressed TFs that have not previously been linked to schizophrenia. In summary, we developed a generalizable approach that integrates GWAS summary statistics with enhancer characteristics to identify risk factors in tissue-specific regulatory regions. AUTHOR SUMMARYEnhancers are regulatory regions that influence gene expression via the binding of transcription factors. Risk for many heritable diseases is enriched in regulatory regions, including enhancers. In this study, we introduce a novel method of testing for association between enhancer attributes and risk and use this method to determine the enhancer characteristics that are associated with risk for schizophrenia. We found that enhancers associated with schizophrenia risk are both evolutionarily conserved and in physical contact with mutation-intolerant genes, many of which have neurodevelopmental functions. Risk-associated enhancers are also AT-rich and contain binding sites for neurodevelopmental transcription factors.

genomics↗

bioRxiv2020

A multimodal cell census and atlas of the mammalian primary motor cortex

We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.

neuroscience↗