Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain, bioRxiv, 2019-08-07
AbstractMicroglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete pro-inflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to age-related and genetic forms of neurodegeneration.
biorxiv neuroscience 100-200-users 2019The critical role of mental imagery in human emotion insights from Aphantasia, bioRxiv, 2019-08-06
AbstractOne proposed function of imagery is to make thoughts more emotionally evocative through sensory simulations. Here we report a novel test of this theory utilizing a special population with no visual imagery Aphantasia. After using multi-method verification of aphantasia, we show that this condition, but not the general population, is associated with a flat-line physiological response to frightening written, but not perceptual scenarios, supporting imagery’s critical role in emotion.
biorxiv neuroscience 100-200-users 2019Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas, bioRxiv, 2019-07-31
AbstractInjury induces retinal Müller glia of cold-blooded, but not mammalian, vertebrates to generate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin conformation in Müller glia from zebrafish, chick and mice using bulk RNA and ATAC-Seq, as well as single-cell RNA-Seq. Cross-species integrative analysis of these data, together with functional validation of candidate genes, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from quiescence to gliosis is a critical stage in acquisition of neurogenic competence, while in mice a dedicated network suppresses this transition and rapidly restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Müller glia to proliferate and robustly generate neurons in adult mice after retinal injury. These comprehensive resources and findings will facilitate the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease.
biorxiv neuroscience 100-200-users 2019Innovations in Primate Interneuron Repertoire, bioRxiv, 2019-07-24
ABSTRACTPrimates and rodents, which descended from a common ancestor more than 90 million years ago, exhibit profound differences in behavior and cognitive capacity. Modifications, specializations, and innovations to brain cell types may have occurred along each lineage. We used Drop-seq to profile RNA expression in more than 184,000 individual telencephalic interneurons from humans, macaques, marmosets, and mice. Conserved interneuron types varied significantly in abundance and RNA expression between mice and primates, but varied much more modestly among primates. In adult primates, the expression patterns of dozens of genes exhibited spatial expression gradients among neocortical interneurons, suggesting that adult neocortical interneurons are imprinted by their local cortical context. In addition, we found that an interneuron type previously associated with the mouse hippocampus—the “ivy cell”, which has neurogliaform characteristics—has become abundant across the neocortex of humans, macaques, and marmosets. The most striking innovation was subcortical we identified an abundant striatal interneuron type in primates that had no molecularly homologous cell population in mouse striatum, cortex, thalamus, or hippocampus. These interneurons, which expressed a unique combination of transcription factors, receptors, and neuropeptides, including the neuropeptide TAC3, constituted almost 30% of striatal interneurons in marmosets and humans. Understanding how gene and cell-type attributes changed or persisted over the evolutionary divergence of primates and rodents will guide the choice of models for human brain disorders and mutations and help to identify the cellular substrates of expanded cognition in humans and other primates.
biorxiv neuroscience 100-200-users 2019ORANGE A CRISPRCas9-based genome editing toolbox for epitope tagging of endogenous proteins in neurons, bioRxiv, 2019-07-19
ABSTRACTThe correct subcellular distribution of protein complexes establishes the complex morphology of neurons and is fundamental to their functioning. Thus, determining the dynamic distribution of proteins is essential to understand neuronal processes. Fluorescence imaging, in particular super-resolution microscopy, has become invaluable to investigate subcellular protein distribution. However, these approaches suffer from the limited ability to efficiently and reliably label endogenous proteins. We developed ORANGE an Open Resource for the Application of Neuronal Genome Editing, that mediates targeted genomic integration of fluorescent tags in neurons. This toolbox includes a knock-in library for in-depth investigation of endogenous protein distribution, and a detailed protocol explaining how knock-in can be developed for novel targets. In combination with super-resolution microscopy, ORANGE revealed the dynamic nanoscale organization of endogenous neuronal signaling molecules, synaptic scaffolding proteins, and neurotransmitter receptors. Thus, ORANGE enables quantitation of expression and distribution for virtually any protein in neurons at high resolution and will significantly further our understanding of neuronal cell biology.
biorxiv neuroscience 200-500-users 2019An integrated brain-machine interface platform with thousands of channels, bioRxiv, 2019-07-17
AbstractBrain-machine interfaces (BMIs) hold promise for the restoration of sensory and motor function and the treatment of neurological disorders, but clinical BMIs have not yet been widely adopted, in part because modest channel counts have limited their potential. In this white paper, we describe Neuralink’s first steps toward a scalable high-bandwidth BMI system. We have built arrays of small and flexible electrode “threads”, with as many as 3,072 electrodes per array distributed across 96 threads. We have also built a neurosurgical robot capable of inserting six threads (192 electrodes) per minute. Each thread can be individually inserted into the brain with micron precision for avoidance of surface vasculature and targeting specific brain regions. The electrode array is packaged into a small implantable device that contains custom chips for low-power on-board amplification and digitization the package for 3,072 channels occupies less than (23 × 18.5 × 2) mm3. A single USB-C cable provides full-bandwidth data streaming from the device, recording from all channels simultaneously. This system has achieved a spiking yield of up to 70% in chronically implanted electrodes. Neuralink’s approach to BMI has unprecedented packaging density and scalability in a clinically relevant package.
biorxiv neuroscience 500+-users 2019