Showing papers in "Nature Neuroscience in 2018"
TL;DR: Using a deep learning approach to track user-defined body parts during various behaviors across multiple species, the authors show that their toolbox, called DeepLabCut, can achieve human accuracy with only a few hundred frames of training data.
Abstract: Quantifying behavior is crucial for many applications in neuroscience. Videography provides easy methods for the observation and recording of animal behavior in diverse settings, yet extracting particular aspects of a behavior for further analysis can be highly time consuming. In motor control studies, humans or other animals are often marked with reflective markers to assist with computer-based tracking, but markers are intrusive, and the number and location of the markers must be determined a priori. Here we present an efficient method for markerless pose estimation based on transfer learning with deep neural networks that achieves excellent results with minimal training data. We demonstrate the versatility of this framework by tracking various body parts in multiple species across a broad collection of behaviors. Remarkably, even when only a small number of frames are labeled (~200), the algorithm achieves excellent tracking performance on test frames that is comparable to human accuracy.
2,303 citations
TL;DR: The immune checkpoints that control microglial functions are considered and how their imbalance and subsequent neuroinflammation leads to neurodegeneration is discussed.
Abstract: The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection Microglia use a defined armamentarium of genes to perform these tasks In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons Injury to neurons in Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy
874 citations
TL;DR: A critical discussion of the role of protein misfolding and aggregation in NDs is provided, in addition to evidence supporting the hypothesis that misfolded aggregates can be transmissible by the prion principle.
Abstract: A hallmark event in neurodegenerative diseases (NDs) is the misfolding, aggregation, and accumulation of proteins, leading to cellular dysfunction, loss of synaptic connections, and brain damage Despite the involvement of distinct proteins in different NDs, the process of protein misfolding and aggregation is remarkably similar A recent breakthrough in the field was the discovery that misfolded protein aggregates can self-propagate through seeding and spread the pathological abnormalities between cells and tissues in a manner akin to the behavior of infectious prions in prion diseases This discovery has vast implications for understanding the mechanisms involved in the initiation and progression of NDs, as well as for the design of novel strategies for treatment and diagnosis In this Review, we provide a critical discussion of the role of protein misfolding and aggregation in NDs Commonalities and differences between distinct protein aggregates will be highlighted, in addition to evidence supporting the hypothesis that misfolded aggregates can be transmissible by the prion principle We will also describe the molecular basis and implications for prion-like conformational strains, cross-interaction between different misfolded proteins in the brain, and how these concepts can be applied to the development of novel strategies for therapy and diagnosis
623 citations
TL;DR: The state of non-invasive brain stimulation research in humans is summarized, some current debates about properties and limitations of these methods are discussed, and recommendations for how these challenges may be addressed are given.
Abstract: In the past three decades, our understanding of brain–behavior relationships has been significantly shaped by research using non-invasive brain stimulation (NIBS) techniques. These methods allow non-invasive and safe modulation of neural processes in the healthy brain, enabling researchers to directly study how experimentally altered neural activity causally affects behavior. This unique property of NIBS methods has, on the one hand, led to groundbreaking findings on the brain basis of various aspects of behavior and has raised interest in possible clinical and practical applications of these methods. On the other hand, it has also triggered increasingly critical debates about the properties and possible limitations of these methods. In this review, we discuss these issues, clarify the challenges associated with the use of currently available NIBS techniques for basic research and practical applications, and provide recommendations for studies using NIBS techniques to establish brain–behavior relationships.
544 citations
TL;DR: An alternative account of how dopamine regulates ongoing behavior is described, which proposes a model that explains how dopamine can serve as both a learning signal and as a critical modulator of motivated decision-making.
Abstract: Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or to move? It is often presumed that motivation involves slow (‘tonic’) dopamine changes, while fast (‘phasic’) dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value and promotes movement even on subsecond timescales. Here I describe an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time.
520 citations
TL;DR: A hypothetical model of Alzheimer’s disease biomarkers is proposed to include brain vasculature as a factor contributing to the disease onset and progression, and a common pathway linking brain vascular contributions to neurodegeneration in multiple Neurodegenerative disorders is suggested.
Abstract: Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning On the other hand, cerebral blood flow shortfalls and blood-brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood-brain barrier integrity Then we examine the role of cerebral blood flow and blood-brain barrier in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis We focus on Alzheimer's disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders Finally, we propose a hypothetical model of Alzheimer's disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders
518 citations
TL;DR: It is demonstrated that meningeal lymphatics drain CSF-derived macromolecules and immune cells and play a key role in regulating neuroinflammation and may represent a new therapeutic target for multiple sclerosis.
Abstract: Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
511 citations
TL;DR: A new theory is presented showing how learning to learn may arise from interactions between prefrontal cortex and the dopamine system, providing a fresh foundation for future research.
Abstract: Over the past 20 years, neuroscience research on reward-based learning has converged on a canonical model, under which the neurotransmitter dopamine ‘stamps in’ associations between situations, actions and rewards by modulating the strength of synaptic connections between neurons. However, a growing number of recent findings have placed this standard model under strain. We now draw on recent advances in artificial intelligence to introduce a new theory of reward-based learning. Here, the dopamine system trains another part of the brain, the prefrontal cortex, to operate as its own free-standing learning system. This new perspective accommodates the findings that motivated the standard model, but also deals gracefully with a wider range of observations, providing a fresh foundation for future research.
441 citations
Raymond K. Walters1, Raymond K. Walters2, Renato Polimanti3, Emma C. Johnson4 +168 more•Institutions (48)
TL;DR: The largest genome-wide association study to date of DSM-IV-diagnosed AD found loci associated with AD and characterized the relationship between AD and other psychiatric and behavioral outcomes, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
Abstract: Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
434 citations
TL;DR: In this paper, a noninvasive neuroimaging measure, T1w/T2w mapping, was used to identify a hierarchical axis linking cortical transcription and anatomy, along which gradients of micro-scale properties may contribute to the macroscale specialization of cortical function.
Abstract: Hierarchy provides a unifying principle for the macroscale organization of anatomical and functional properties across primate cortex, yet microscale bases of specialization across human cortex are poorly understood. Anatomical hierarchy is conventionally informed by invasive tract-tracing measurements, creating a need for a principled proxy measure in humans. Moreover, cortex exhibits marked interareal variation in gene expression, yet organizing principles of cortical transcription remain unclear. We hypothesized that specialization of cortical microcircuitry involves hierarchical gradients of gene expression. We found that a noninvasive neuroimaging measure—MRI-derived T1-weighted/T2-weighted (T1w/T2w) mapping—reliably indexes anatomical hierarchy, and it captures the dominant pattern of transcriptional variation across human cortex. We found hierarchical gradients in expression profiles of genes related to microcircuit function, consistent with monkey microanatomy, and implicated in neuropsychiatric disorders. Our findings identify a hierarchical axis linking cortical transcription and anatomy, along which gradients of microscale properties may contribute to the macroscale specialization of cortical function.
414 citations
TL;DR: A new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic platform is presented to facilitate the development of more precise human brain models for basic mechanistic studies in neural–glial interactions and drug discovery.
Abstract: Alzheimer's disease (AD) is characterized by beta-amyloid accumulation, phosphorylated tau formation, hyperactivation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood, partially due to the lack of relevant models that can comprehensively recapitulate multistage intercellular interactions in human AD brains. Here we present a new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic platform. Our model provided key representative AD features: beta-amyloid aggregation, phosphorylated tau accumulation, and neuroinflammatory activity. In particular, the model mirrored microglial recruitment, neurotoxic activities such as axonal cleavage, and NO release damaging AD neurons and astrocytes. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural-glial interactions and drug discovery.
TL;DR: The results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.
Abstract: Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.
TL;DR: The construction and validation of a molecular network of the aging human frontal cortex is reported, constructed and validated from RNA sequence data from 478 individuals and identified genes that affect cognitive decline or neuropathology in Alzheimer's disease.
Abstract: There is a need for new therapeutic targets with which to prevent Alzheimer’s disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.
TL;DR: Using longitudinal in vivo two-photon imaging of oligodendrocytes and their progenitors in the mouse cerebral cortex, it is shown that myelination is an inefficient and extended process, with half of the final complement of oligo-myelination generated after 4 months of age.
Abstract: Oligodendrocyte generation in the adult CNS provides a means to adapt the properties of circuits to changes in life experience. However, little is known about the dynamics of oligodendrocytes and the extent of myelin remodeling in the mature brain. Using longitudinal in vivo two-photon imaging of oligodendrocytes and their progenitors in the mouse cerebral cortex, we show that myelination is an inefficient and extended process, with half of the final complement of oligodendrocytes generated after 4 months of age. Oligodendrocytes that successfully integrated formed new sheaths on unmyelinated and sparsely myelinated axons, and they were extremely stable, gradually changing the pattern of myelination. Sensory enrichment robustly increased oligodendrocyte integration, but did not change the length of existing sheaths. This experience-dependent enhancement of myelination in the mature cortex may accelerate information transfer in these circuits and strengthen the ability of axons to sustain activity by providing additional metabolic support.
Radboud University Nijmegen1, University of Amsterdam2, QIMR Berghofer Medical Research Institute3, VU University Amsterdam4, University of California, San Diego5, University of Bristol6, University of Cambridge7, University of Chicago8, Vanderbilt University9, St. Joseph's Healthcare Hamilton10, University of Illinois at Urbana–Champaign11, Utrecht University12, University Medical Center Groningen13, Washington University in St. Louis14, University of Tartu15, University of Queensland16, Hospital for Sick Children17, University of Toronto18, Carlos III Health Institute19, Autonomous University of Barcelona20, University of Helsinki21, King's College London22, Yale University23, Virginia Commonwealth University24
TL;DR: A GWAS of lifetime cannabis use reveals new risk loci, shows that cannabis use has genetic overlap with smoking and alcohol use, and indicates that the likelihood of initiating cannabis use is causally influenced by schizophrenia.
Abstract: Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.
TL;DR: BioID uses proximity-dependent biotin identification to interrogate the interactome of detergent-insoluble TDP-43 aggregates and finds them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery.
Abstract: The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.
TL;DR: The authors argue that intracranial EEG recordings in humans add unique information beyond invasive recordings in animal models and noninvasive human research, including anatomically precise dynamics and network interactions of neuronal populations.
Abstract: Intracranial electroencephalography (iEEG), also known as electrocorticography when using subdural grid electrodes or stereotactic EEG when using depth electrodes, is blossoming in various fields of human neuroscience. In this article, we highlight the potentials of iEEG in exploring functions of the human brain while also considering its limitations. The iEEG signal provides anatomically precise information about the selective engagement of neuronal populations at the millimeter scale and the temporal dynamics of their engagement at the millisecond scale. If several nodes of a given network are monitored simultaneously with implanted electrodes, the iEEG signals can also reveal information about functional interactions within and across networks during different stages of neural computation. As such, human iEEG can complement other methods of neuroscience beyond simply replicating what is already known, or can be known, from noninvasive lines of research in humans or from invasive recordings in nonhuman mammalian brains.
TL;DR: This work details the emerging understanding of the underlying biology of selective neuronal vulnerability and outlines some of the areas in which the understanding is incomplete.
Abstract: Neurodegenerative diseases have two general characteristics that are so fundamental we usually take them for granted The first is that the pathology associated with the disease only affects particular neurons (‘selective neuronal vulnerability’); the second is that the pathology worsens with time and impacts more regions in a stereotypical and predictable fashion The mechanisms underpinning selective neuronal and regional vulnerability have been difficult to dissect, but the recent application of whole-genome technologies, the development of mouse models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable neurons are beginning to shed some light on these fundamental features of neurodegenerative diseases Here we detail our emerging understanding of the underlying biology of selective neuronal vulnerability and outline some of the areas in which our understanding is incomplete Neurodegenerative diseases impact specific cell populations within the brain However, not all cells within the population are impacted, a phenomenon called selective cellular vulnerability The molecular basis of this vulnerability is discussed
TL;DR: It is demonstrated that the newly formed microglia are actually solely derived from residualmicroglia, suggesting the absence of microglial progenitor cells in the adult brain.
Abstract: Newborn microglia rapidly replenish the whole brain after selective elimination of most microglia (>99%) in adult mice. Previous studies reported that repopulated microglia were largely derived from microglial progenitor cells expressing nestin in the brain. However, the origin of these repopulated microglia has been hotly debated. In this study, we investigated the origin of repopulated microglia by a series of fate-mapping approaches. We first excluded the blood origin of repopulated microglia via parabiosis. With different transgenic mouse lines, we then demonstrated that all repopulated microglia were derived from the proliferation of the few surviving microglia (<1%). Despite a transient pattern of nestin expression in newly forming microglia, none of repopulated microglia were derived from nestin-positive non-microglial cells. In summary, we conclude that repopulated microglia are solely derived from residual microglia rather than de novo progenitors, suggesting the absence of microglial progenitor cells in the adult brain.
TL;DR: It is reported that temporal flexibility emerges in rhesus monkeys from the ability of their brain to flexibly control the speed at which cortical responses unfold in time.
Abstract: Musicians can perform at different tempos, speakers can control the cadence of their speech, and children can flexibly vary their temporal expectations of events. To understand the neural basis of such flexibility, we recorded from the medial frontal cortex of nonhuman primates trained to produce different time intervals with different effectors. Neural responses were heterogeneous, nonlinear, and complex, and they exhibited a remarkable form of temporal invariance: firing rate profiles were temporally scaled to match the produced intervals. Recording from downstream neurons in the caudate and from thalamic neurons projecting to the medial frontal cortex indicated that this phenomenon originates within cortical networks. Recurrent neural network models trained to perform the task revealed that temporal scaling emerges from nonlinearities in the network and that the degree of scaling is controlled by the strength of external input. These findings demonstrate a simple and general mechanism for conferring temporal flexibility upon sensorimotor and cognitive functions.
TL;DR: It is shown that early developmental neurogenesis in the dentate gyrus of the hippocampus is largely conserved in the adult, but with a perinatal transformation of stem cells to an adult type.
Abstract: The dentate gyrus of the hippocampus is a brain region in which neurogenesis persists into adulthood; however, the relationship between developmental and adult dentate gyrus neurogenesis has not been examined in detail. Here we used single-cell RNA sequencing to reveal the molecular dynamics and diversity of dentate gyrus cell types in perinatal, juvenile, and adult mice. We found distinct quiescent and proliferating progenitor cell types, linked by transient intermediate states to neuroblast stages and fully mature granule cells. We observed shifts in the molecular identity of quiescent and proliferating radial glia and granule cells during the postnatal period that were then maintained through adult stages. In contrast, intermediate progenitor cells, neuroblasts, and immature granule cells were nearly indistinguishable at all ages. These findings demonstrate the fundamental similarity of postnatal and adult neurogenesis in the hippocampus and pinpoint the early postnatal transformation of radial glia from embryonic progenitors to adult quiescent stem cells.
TL;DR: The authors review the current state of rodent models for AD, PD, FTD, and ALS and discusses the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.
Abstract: Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.
TL;DR: An essential function for m6A mRNA modification in promoting neural stem cell proliferation is demonstrated and interactions between m 6A and histone modification as a novel gene regulatory mechanism are revealed.
Abstract: Internal N6-methyladenosine (m6A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m6A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking Mettl14 displayed markedly decreased proliferation and premature differentiation, suggesting that m6A modification enhances NSC self-renewal. Decreases in the NSC pool led to a decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in Mettl14 knockout versus control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Finally, we found that m6A regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for m6A in development and reveal m6A-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells.
TL;DR: Using single-cell RNA-seq, the authors found that neuron types build the dorsal horn by a discrete layering and to be differentially engaged by noxious heat and cold.
Abstract: The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.
TL;DR: Cortical myelin remodeling is protracted throughout life, potentially playing critical roles in neuronal network homeostasis and the gradual loss of internodes and myelin degeneration in aging could contribute significantly to brain pathogenesis.
Abstract: Axonal myelin increases neural processing speed and efficiency. It is unknown whether patterns of myelin distribution are fixed or whether myelinating oligodendrocytes are continually generated in adulthood and maintain the capacity for structural remodeling. Using high-resolution, intravital label-free and fluorescence optical imaging in mouse cortex, we demonstrate lifelong oligodendrocyte generation occurring in parallel with structural plasticity of individual myelin internodes. Continuous internode formation occurred on both partially myelinated and unmyelinated axons, and the total myelin coverage along individual axons progressed up to two years of age. After peak myelination, gradual oligodendrocyte death and myelin degeneration in aging were associated with pronounced internode loss and myelin debris accumulation within microglia. Thus, cortical myelin remodeling is protracted throughout life, potentially playing critical roles in neuronal network homeostasis. The gradual loss of internodes and myelin degeneration in aging could contribute significantly to brain pathogenesis.
TL;DR: The authors review recent work at the intersection of cognitive science, computational neuroscience and artificial intelligence that develops and tests computational models mimicking neural and cognitive function during a wide range of tasks.
Abstract: To learn how cognition is implemented in the brain, we must build computational models that can perform cognitive tasks, and test such models with brain and behavioral experiments. Cognitive science has developed computational models that decompose cognition into functional components. Computational neuroscience has modeled how interacting neurons can implement elementary components of cognition. It is time to assemble the pieces of the puzzle of brain computation and to better integrate these separate disciplines. Modern technologies enable us to measure and manipulate brain activity in unprecedentedly rich ways in animals and humans. However, experiments will yield theoretical insight only when employed to test brain-computational models. Here we review recent work in the intersection of cognitive science, computational neuroscience and artificial intelligence. Computational models that mimic brain information processing during perceptual, cognitive and control tasks are beginning to be developed and tested with brain and behavioral data.
TL;DR: The intricate genotype–phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies are reviewed, revealing shared pathogenic mechanisms and emerging therapeutic opportunities and challenges.
Abstract: Neurodegenerative diseases cause progressive loss of cognitive and/or motor function and pose major challenges for societies with rapidly aging populations. Human genetics studies have shown that disease-causing rare mutations and risk-associated common alleles overlap in different neurodegenerative disorders. Here we review the intricate genotype-phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies. Shared pathological mechanisms include defective protein quality-control and degradation pathways, dysfunctional mitochondrial homeostasis, stress granules, and maladaptive innate immune responses. Research efforts have started to bear fruit, as shown by recent treatment successes and an encouraging therapeutic outlook.
TL;DR: This study describes single-nucleus ATAC-seq, a combinatorial barcoding-assisted single-cell assay for transposase-accessible chromatin that is optimized for use on flash-frozen primary tissue samples used to examine gene regulation in 15,000 nuclei comprising 20 distinct cell types in the developing mouse forebrain.
Abstract: Analysis of chromatin accessibility can reveal transcriptional regulatory sequences, but heterogeneity of primary tissues poses a significant challenge in mapping the precise chromatin landscape in specific cell types. Here we report single-nucleus ATAC-seq, a combinatorial barcoding-assisted single-cell assay for transposase-accessible chromatin that is optimized for use on flash-frozen primary tissue samples. We apply this technique to the mouse forebrain through eight developmental stages. Through analysis of more than 15,000 nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell types. We further define cell-type-specific transcriptional regulatory sequences, infer potential master transcriptional regulators and delineate developmental changes in forebrain cellular composition. Our results provide insight into the molecular and cellular dynamics that underlie forebrain development in the mouse and establish technical and analytical frameworks that are broadly applicable to other heterogeneous tissues.
TL;DR: It is shown that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition, which highlights a key role of epigenetic mechanisms in preventing microglian-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.
Abstract: The rapid elimination of dying neurons and nonfunctional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene-expression programs supporting clearance activity. We provide evidence that the polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 leads to aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.
TL;DR: The authors surveyed gene expression across cortical development and in individuals with schizophrenia, finding 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development.
Abstract: Genome-wide association studies have identified 108 schizophrenia risk loci, but biological mechanisms for individual loci are largely unknown Using developmental, genetic and illness-based RNA sequencing expression analysis in human brain, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and postnatal life We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated We leveraged this general eQTL database to show that 481% of risk variants for schizophrenia associate with nearby expression We lastly found 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development These findings together offer genetics- and diagnosis-related targets for better modeling of schizophrenia risk This resource is publicly available at http://eqtlbrainseqorg/phase1