Dan Geschwind

The cerebral cortex underlies many of our unique strengths and vulnerabilities, but efforts to understand human cortical organization are challenged by reliance on incompatible measurement methods at different spatial scales. Macroscale features such as cortical folding and functional activation are accessed through spatially dense neuroimaging maps, whereas microscale cellular and molecular features are typically measured with sparse postmortem sampling. Here, we integrate these distinct windows on brain organization by building upon existing postmortem data to impute, validate, and analyze a library of spatially dense neuroimaging-like maps of human cortical gene expression. These maps allow spatially unbiased discovery of cortical zones with extreme transcriptional profiles or unusually rapid transcriptional change which index distinct microstructure and predict neuroimaging measures of cortical folding and functional activation. Modules of spatially coexpressed genes define a family of canonical expression maps that integrate diverse spatial scales and temporal epochs of human brain organization–ranging from protein–protein interactions to large-scale systems for cognitive processing. These module maps also parse neuropsychiatric risk genes into subsets which tag distinct cyto-laminar features and differentially predict the location of altered cortical anatomy and gene expression in patients. Taken together, the methods, resources, and findings described here advance our understanding of human cortical organization and offer flexible bridges to connect scientific fields operating at different spatial scales of human brain research.

Glioblastoma (GBM), a universally fatal brain cancer, infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression1-6. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic7-9. The extent of integration of GBM cells into brain-wide neuronal circuitry is not well understood. Here we applied a rabies virus-mediated retrograde monosynaptic tracing approach10-12 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrated into brain-wide neuronal circuits and exhibited diverse local and long-range connectivity. Beyond glutamatergic inputs, we identified a variety of neuromodulatory inputs across the brain, including cholinergic inputs from the basal forebrain. Acute acetylcholine stimulation induced sustained calcium oscillations and long-lasting transcriptional reprogramming of GBM cells into a more invasive state via the metabotropic CHRM3 receptor. CHRM3 downregulation suppressed GBM cell invasion, proliferation, and survival in vitro and in vivo. Together, these results reveal the capacity of human GBM cells to rapidly and robustly integrate into anatomically and molecularly diverse neuronal circuitry in the adult brain and support a model wherein rapid synapse formation onto GBM cells and transient activation of upstream neurons may lead to a long-lasting increase in fitness to promote tumor infiltration and progression.

In adult mammals, injured retinal ganglion cells (RGCs) fail to spontaneously regrow severed axons, resulting in permanent visual deficits. Robust axon growth, however, is observed after intra-ocular injection of particulate β-glucan isolated from yeast. Blood-borne myeloid cells rapidly respond to β-glucan, releasing numerous pro-regenerative factors. Unfortunately, the pro-regenerative effects are undermined by retinal damage inflicted by an overactive immune system. Here, we demonstrate that protection of the inflamed vasculature promotes immune-mediated RGC regeneration. In the absence of microglia, leakiness of the blood-retina barrier increases, pro-inflammatory neutrophils are elevated, and RGC regeneration is reduced. Functional ablation of the complement receptor 3 (CD11b/integrin-αM), but not the complement components C1q−/− or C3−/−, reduces ocular inflammation, protects the blood-retina …

The original version of this Article omitted the Competing Interests below:‘XJZ and WHW are board members for EarlyDiagnostics, Inc. XJZ has an executive leadership position at EarlyDiagnostics, Inc.’and ‘XJZ, WL, WHW, and FA are stockholders of EarlyDiagnostics, Inc. MLS, WZ, SL, C.-CL, Y. Zhou, QL, XN have stock options with EarlyDiagnostics, Inc’. The statement:‘The authors have filed a patent application on methods described in this manuscript’has been replaced with the statement:‘XJZ, MLS, Y. Zhou, XN, and WZ are inventors on a patent application submitted by the Regents of the University of California and licensed to EarlyDiagnostics, Inc.(Patent No. US20210404007A1). PSL performed summer internships in EarlyDiagnostics, Inc. in 2021 and 2022’. in the corrected article. In addition, the original Competing Interests section contained the incorrect author initials ‘SL’, instead of ‘W. L’.

Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic …

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ∼250 disease-risk genes and drug targets with associated cell types.Summary Figure

Background Previous studies have established a strong link between late-onset epilepsy (LOE) and Alzheimer's disease (AD). However, their shared genetic risk beyond the APOE gene remains unclear. Our study sought to examine the shared genetic factors of AD and LOE, interpret the biological pathways involved, and evaluate how AD onset may be mediated by LOE and shared genetic risks. Methods We defined phenotypes using phecodes mapped from diagnosis codes, with patients' records aged 60-90. A two-step Least Absolute Shrinkage and Selection Operator (LASSO) workflow was used to identify shared genetic variants based on prior AD GWAS integrated with functional genomic data. We calculated an AD-LOE shared risk score and used it as a proxy in a causal mediation analysis. We used electronic health records from an academic health center (UCLA Health) for discovery analyses and validated our findings in a multi-institutional EHR database (All of Us). Results The two-step LASSO method identified 34 shared genetic loci between AD and LOE, including the APOE region. These loci were mapped to 65 genes, which showed enrichment in molecular functions and pathways such as tau protein binding and lipoprotein metabolism. Individuals with high predicted shared risk scores have a higher risk of developing AD, LOE, or both in their later life compared to those with low-risk scores. LOE partially mediates the effect of AD-LOE shared genetic risk on AD (15% proportion mediated on average). Validation results from All of Us were consistent with findings from the UCLA sample. Conclusions We employed a machine learning …

Severe psychiatric illnesses, for instance schizophrenia, and affective diseases or autism spectrum disorders, have been associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Effects in juvenile mice can elucidate how erythropoietin (EPO) might aid in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, conceivably explaining mitigation of neuropsychiatric diseases. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing ~12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand …