Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons

We developed an automatic morphometric reconstruction pipeline, Pop-Rec, and used it to study the morphologies of cortical cholinergic VIP/ChAT interneurons (VChIs). Cholinergic networks control high cognitive functions, but their local modulation and stress-driven plasticity patterns remained elusive. Reconstructing thousands of local VChIs registered to their exact coordinates in multiple cleared murine cortices highlighted distinct populations of bipolar and multipolar VChIs which differed in their dendritic spatial organization. Following mild unilateral whisker deprivation, Pop-Rec found both ipsi-and contra-lateral VChI dendritic arborization changes. Furthermore, RNA-seq of FACS-sorted VChIs showed differentially expressed dendritic, synapse and axon-modulating transcripts in whisker-deprived mice. Indicating novel steady-state morphological roles, those genes also clustered distinctly in naïve single cell VChIs. This VChIs “morpheome” atlas is the first example of unbiased analysis of neuronal populations and holds the possibility to compare neuronal structure-function relationships across experimental conditions.

[1]  Christian Borgs,et al.  Discovering Neuronal Cell Types and Their Gene Expression Profiles Using a Spatial Point Process Mixture Model , 2017 .

[2]  Chiung-Ya Chen,et al.  TLR7 Negatively Regulates Dendrite Outgrowth through the Myd88–c-Fos–IL-6 Pathway , 2013, The Journal of Neuroscience.

[3]  Nested Case-control Study , 1992 .

[4]  Darren J. Burgess,et al.  Spatial transcriptomics coming of age , 2019, Nature Reviews Genetics.

[5]  N. Neff,et al.  Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing , 2018, Neuron.

[6]  C. Petersen,et al.  Cholinergic signals in mouse barrel cortex during active whisker sensing. , 2014, Cell reports.

[7]  J. Hippisley-Cox,et al.  Anticholinergic Drug Exposure and the Risk of Dementia , 2019, JAMA internal medicine.

[8]  Sean L. Hill,et al.  BigNeuron: Large-Scale 3D Neuron Reconstruction from Optical Microscopy Images , 2015, Neuron.

[9]  Rodney W. Johnson,et al.  Influenza Infection Induces Neuroinflammation, Alters Hippocampal Neuron Morphology, and Impairs Cognition in Adult Mice , 2012, The Journal of Neuroscience.

[10]  O. Vitolo,et al.  Dendrite and dendritic spine alterations in alzheimer models , 2004, Journal of neurocytology.

[11]  William R. Gray Roncal,et al.  Saturated Reconstruction of a Volume of Neocortex , 2015, Cell.

[12]  D. Sholl,et al.  Pattern Discrimination and the Visual Cortex , 1953, Nature.

[13]  Cheuk Y. Tang,et al.  Mapping of Brain Activity by Automated Volume Analysis of Immediate Early Genes , 2016, Cell.

[14]  P. Gaspar,et al.  Development and critical period plasticity of the barrel cortex , 2012, The European journal of neuroscience.

[15]  J. Changeux,et al.  Enhanced Hemicholinium Binding and Attenuated Dendrite Branching in Cognitively Impaired Acetylcholinesterase‐Transgenic Mice , 1997, Journal of neurochemistry.

[16]  I. Whishaw,et al.  The Dalila effect: C57BL6 mice barber whiskers by plucking , 2000, Behavioural Brain Research.

[17]  M. Piechota,et al.  Kainic Acid Induces mTORC1-Dependent Expression of Elmo1 in Hippocampal Neurons , 2016, Molecular Neurobiology.

[18]  A. Becchetti,et al.  Developmental and neurochemical features of cholinergic neurons in the murine cerebral cortex , 2009, BMC Neuroscience.

[19]  Alexander Borst,et al.  One Rule to Grow Them All: A General Theory of Neuronal Branching and Its Practical Application , 2010, PLoS Comput. Biol..

[20]  Idan Segev,et al.  Dendrites Impact the Encoding Capabilities of the Axon , 2014, The Journal of Neuroscience.

[21]  Jochen F. Staiger,et al.  Characterizing VIP Neurons in the Barrel Cortex of VIPcre/tdTomato Mice Reveals Layer-Specific Differences , 2015, Cerebral cortex.

[22]  Marshall G. Hussain Shuler,et al.  Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition , 2015, The Journal of Neuroscience.

[23]  Hannah Monyer,et al.  Functional Characterization of Intrinsic Cholinergic Interneurons in the Cortex , 2007, The Journal of Neuroscience.

[24]  Joakim Lundeberg,et al.  Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease , 2020, Cell.

[25]  H. Soreq,et al.  Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder , 2019, Cell reports.

[26]  S. Quake,et al.  A survey of human brain transcriptome diversity at the single cell level , 2015, Proceedings of the National Academy of Sciences.

[27]  Aviv Regev,et al.  Massively-parallel single nucleus RNA-seq with DroNc-seq , 2017, Nature Methods.

[28]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[29]  H. Brenhouse,et al.  Sex-specific effects of early life stress on social interaction and prefrontal cortex dendritic morphology in young rats , 2016, Behavioural Brain Research.

[30]  A. Tanay,et al.  Single cell Hi-C reveals cell-to-cell variability in chromosome structure , 2013, Nature.

[31]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[32]  James G. King,et al.  Reconstruction and Simulation of Neocortical Microcircuitry , 2015, Cell.

[33]  Hang Zhou,et al.  NeuroGPS-Tree: automatic reconstruction of large-scale neuronal populations with dense neurites , 2015, Nature Methods.

[34]  M. London,et al.  Intensify3D: Normalizing signal intensity in large heterogenic image stacks , 2018, Scientific Reports.

[35]  Hongkui Zeng,et al.  Generation of a whole-brain atlas for the cholinergic system and mesoscopic projectome analysis of basal forebrain cholinergic neurons , 2017, Proceedings of the National Academy of Sciences.

[36]  D. Tam,et al.  Sensory deprivation differentially impacts the dendritic development of pyramidal versus non-pyramidal neurons in layer 6 of mouse barrel cortex , 2011, Brain Structure and Function.

[37]  Allan R. Jones,et al.  A mesoscale connectome of the mouse brain , 2014, Nature.

[38]  E. Susaki,et al.  Whole-Brain Imaging with Single-Cell Resolution Using Chemical Cocktails and Computational Analysis , 2014, Cell.

[39]  H. Fibiger,et al.  A comparison of the distribution of central cholinergic neurons as demonstrated by acetylcholinesterase pharmacohistochemistry and choline acetyltransferase immunohistochemistry , 1983, Brain Research Bulletin.

[40]  Alzheimer's Disease Neuroimaging Initiative,et al.  Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease , 2011, Molecular Psychiatry.

[41]  K. Deisseroth,et al.  Advanced CLARITY for rapid and high-resolution imaging of intact tissues , 2014, Nature Protocols.

[42]  W. B. Lindquist,et al.  Experience-dependent changes in basal dendritic branching of layer 2/3 pyramidal neurons during a critical period for developmental plasticity in rat barrel cortex. , 2004, Cerebral cortex.

[43]  B. Sabatini,et al.  Corelease of acetylcholine and GABA from cholinergic forebrain neurons , 2015, eLife.

[44]  D. Sholl.  Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953, Journal of anatomy.

[45]  Hanchuan Peng,et al.  Extensible visualization and analysis for multidimensional images using Vaa3D , 2014, Nature Protocols.

[46]  B. Sabatini,et al.  Target-specific co-transmission of acetylcholine and GABA from a subset of cortical VIP+ interneurons , 2018, bioRxiv.

[47]  Hiroshi Sekiya,et al.  A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing , 2018, Nature Neuroscience.

[48]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[49]  Karel Svoboda,et al.  A platform for brain-wide imaging and reconstruction of individual neurons , 2016, eLife.

[50]  M. Helmstaedter,et al.  Dense connectomic reconstruction in layer 4 of the somatosensory cortex , 2018, Science.

[51]  N. Renier,et al.  iDISCO: A Simple, Rapid Method to Immunolabel Large Tissue Samples for Volume Imaging , 2014, Cell.

[52]  Alexander Borst,et al.  The TREES Toolbox—Probing the Basis of Axonal and Dendritic Branching , 2011, Neuroinformatics.

[53]  Sholl Da.  Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953 .

[54]  C. Geula,et al.  Cortical cholinergic fibers in aging and Alzheimer's disease: A morphometric study , 1989, Neuroscience.

[55]  Allan R. Jones,et al.  Shared and distinct transcriptomic cell types across neocortical areas , 2018, Nature.

[56]  B. Sabatini,et al.  Author response: Corelease of acetylcholine and GABA from cholinergic forebrain neurons , 2015 .

[57]  Kevin M. Dean,et al.  Light-Sheet Microscopy of Cleared Tissues with Isotropic, Subcellular Resolution , 2019, Nature Methods.

[58]  A. Regev,et al.  A SINGLE-CELL-BASED ATLAS OF HUMAN MICROGLIAL STATES SHOWS DIVERGENT ASSOCIATIONS WITH AGING-RELATED NEUROPATHOLOGIES AND DEMENTIA , 2018, Alzheimer's & Dementia.

[59]  R. Hertzano,et al.  Semaphorin-5B Controls Spiral Ganglion Neuron Branch Refinement during Development , 2019, The Journal of Neuroscience.

[60]  M. London,et al.  Barrel cortex VIP/ChAT interneurons suppress sensory responses in vivo , 2020, PLoS biology.

[61]  L. C. Katz,et al.  Destabilization of Cortical Dendrites and Spines by BDNF , 1999, Neuron.

[62]  Brian R. Lee,et al.  Classification of electrophysiological and morphological neuron types in the mouse visual cortex , 2019, Nature Neuroscience.

[63]  I. Vida,et al.  The RNA-binding protein ARPP21 controls dendritic branching by functionally opposing the miRNA it hosts , 2018, Nature Communications.