3D synaptic organization of layer III of the human anterior cingulate and temporopolar cortex

The human anterior cingulate and temporopolar cortices have been proposed as highly connected nodes involved in high-order cognitive functions, but their synaptic organization is still basically unknown due to the difficulties involved in studying the human brain. Using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) to study the synaptic organization of the human brain obtained with a short post-mortem delay allows excellent results to be obtained. We have used this technology to analyze the neuropil (where the vast majority of synapses are found) of layer III of the anterior cingulate cortex (Brodmann’s area 24) and the temporopolar cortex, including the temporal pole (Brodmann’s area 38 ventral and dorsal) and anterior middle temporal gyrus (Brodmann’s area 21). Our results, based on 6695 synapses fully reconstructed in 3D, revealed that Brodmann’s areas 24, 21 and ventral area 38 showed similar synaptic density and synaptic size, whereas dorsal area 38 displayed the highest synaptic density and the smallest synaptic size. However, the proportion of the different types of synapses (excitatory and inhibitory), the postsynaptic targets and the shapes of excitatory and inhibitory synapses were similar, regardless of the region examined. These observations indicate that certain aspects of the synaptic organization are rather homogeneous, whereas others show specific variations across cortical regions. Since not all data obtained in a given cortical region can be extrapolated to other cortical regions, further studies on the other cortical regions and layers are necessary to better understand the functional organization of the human cerebral cortex.

[1]  K. Harris,et al.  Dually innervated dendritic spines develop in the absence of excitatory activity and resist plasticity through tonic inhibitory crosstalk , 2022, Neuron.

[2]  M. Mesulam Temporopolar regions of the human brain. , 2022, Brain : a journal of neurology.

[3]  J. DeFelipe,et al.  Quantitative analysis of the GABAergic innervation of the soma and axon initial segment of pyramidal cells in the human and mouse neocortex. , 2022, Cerebral cortex.

[4]  T. Pfeffer,et al.  An increase of inhibition drives the developmental decorrelation of neural activity , 2022, eLife.

[5]  M. Brecht,et al.  Cortical synapses of the world's smallest mammal: An FIB/SEM study in the Etruscan shrew , 2022, bioRxiv.

[6]  T. Komiyama,et al.  Learning binds new inputs into functional synaptic clusters via spinogenesis , 2022, Nature Neuroscience.

[7]  James G. King,et al.  A calcium-based plasticity model for predicting long-term potentiation and depression in the neocortex , 2022, Nature Communications.

[8]  S. Cichon,et al.  Combined analysis of cytoarchitectonic, molecular and transcriptomic patterns reveal differences in brain organization across human functional brain systems , 2022, NeuroImage.

[9]  P. Somogyi,et al.  Differential effects of group III metabotropic glutamate receptors on spontaneous inhibitory synaptic currents in spine-innervating double bouquet and parvalbumin-expressing dendrite-targeting GABAergic interneurons in human neocortex , 2022, bioRxiv.

[10]  H. Barbas,et al.  Pathways for Memory, Cognition and Emotional Context: Hippocampal, Subgenual Area 25, and Amygdalar Axons Show Unique Interactions in the Primate Thalamic Reuniens Nucleus , 2021, The Journal of Neuroscience.

[11]  J. Fuster Cognitive Networks (Cognits) Process and Maintain Working Memory , 2022, Frontiers in Neural Circuits.

[12]  O. Sporns,et al.  Modular Community Structure of the Face Network Supports Face Recognition. , 2021, Cerebral cortex.

[13]  N. Censor,et al.  Intrinsic Functional Connectivity of the Anterior Cingulate Cortex Is Associated with Tolerance to Distress , 2021, eNeuro.

[14]  J. DeFelipe,et al.  Variation in Pyramidal Cell Morphology Across the Human Anterior Temporal Lobe , 2021, Cerebral cortex.

[15]  J. DeFelipe,et al.  Three-Dimensional Synaptic Organization of Layer III of the Human Temporal Neocortex , 2021, bioRxiv.

[16]  J. DeFelipe,et al.  Three-dimensional analysis of synaptic organization in the hippocampal CA1 field in Alzheimer’s disease , 2020, Brain : a journal of neurology.

[17]  Yohan J. John,et al.  Pathways for Contextual Memory: The Primate Hippocampal Pathway to Anterior Cingulate Cortex. , 2020, Cerebral cortex.

[18]  Jeffery A. Hall,et al.  A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain , 2020, PLoS biology.

[19]  Samridha,et al.  Semantic Network , 2020, Regular.

[20]  T. Sumi,et al.  Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors , 2020, Scientific Reports.

[21]  J. DeFelipe,et al.  3D Ultrastructural Study of Synapses in the Human Entorhinal Cortex , 2020, bioRxiv.

[22]  J. DeFelipe,et al.  Three-dimensional synaptic organization of the human hippocampal CA1 field , 2020, bioRxiv.

[23]  Christine Grienberger,et al.  Synaptic Plasticity Forms and Functions. , 2020, Annual review of neuroscience.

[24]  Jose R. Rodriguez,et al.  Estimation of the number of synapses in the hippocampus and brain-wide by volume electron microscopy and genetic labeling , 2020, Scientific Reports.

[25]  M. Larkum,et al.  Dendritic action potentials and computation in human layer 2/3 cortical neurons , 2020, Science.

[26]  J. Lübke,et al.  Ultrastructural heterogeneity of layer 4 excitatory synaptic boutons in the adult human temporal lobe neocortex , 2019, eLife.

[27]  J. DeFelipe,et al.  3D Electron Microscopy Study of Synaptic Organization of the Normal Human Transentorhinal Cortex and Its Possible Alterations in Alzheimer’s Disease , 2019, eNeuro.

[28]  H. Alle,et al.  High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp , 2019, bioRxiv.

[29]  J. Rubenstein,et al.  Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders , 2019, Molecular Psychiatry.

[30]  P. Bartolomeo,et al.  Hemispheric lateralization of attention processes in the human brain. , 2019, Current opinion in psychology.

[31]  Pascal Fua,et al.  The effects of aging on neuropil structure in mouse somatosensory cortex—A 3D electron microscopy analysis of layer 1 , 2018, PloS one.

[32]  J. DeFelipe,et al.  Three-dimensional analysis of synapses in the transentorhinal cortex of Alzheimer’s disease patients , 2018, Acta neuropathologica communications.

[33]  Guy Eyal,et al.  Human Cortical Pyramidal Neurons: From Spines to Spikes via Models , 2018, bioRxiv.

[34]  Jose R. Rodriguez,et al.  Study of the Size and Shape of Synapses in the Juvenile Rat Somatosensory Cortex with 3D Electron Microscopy , 2018, eNeuro.

[35]  Hua Hu,et al.  Synaptic Integration in Cortical Inhibitory Neuron Dendrites , 2018, Neuroscience.

[36]  K. Zilles,et al.  Multiple Transmitter Receptors in Regions and Layers of the Human Cerebral Cortex , 2017, Front. Neuroanat..

[37]  R. D. D'Souza,et al.  A Laminar Organization for Selective Cortico-Cortical Communication , 2017, Front. Neuroanat..

[38]  Nicola Palomero-Gallagher,et al.  Cortical layers: Cyto-, myelo-, receptor- and synaptic architecture in human cortical areas , 2017, NeuroImage.

[39]  J DeFelipe,et al.  Volume electron microscopy of the distribution of synapses in the neuropil of the juvenile rat somatosensory cortex , 2017, Brain Structure and Function.

[40]  M. Medalla,et al.  Comparative ultrastructural features of excitatory synapses in the visual and frontal cortices of the adult mouse and monkey , 2017, The Journal of comparative neurology.

[41]  D. Stoyan Spatial Point Patterns: Methodology and Applications with R. A. Baddeley, E. Rubak, R. Turner (2016). Boca Raton, FL: CRC Press. ISBN: 978‐1‐4822‐1020‐0 (Hardback). , 2017 .

[42]  Virgilio Gómez-Rubio,et al.  Spatial Point Patterns: Methodology and Applications with R , 2016 .

[43]  C. Bielza,et al.  Dendritic-branching angles of pyramidal neurons of the human cerebral cortex , 2016, Brain Structure and Function.

[44]  R. Tremblay,et al.  GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits , 2016, Neuron.

[45]  Paul Hoffman,et al.  The Semantic Network at Work and Rest: Differential Connectivity of Anterior Temporal Lobe Subregions , 2016, The Journal of Neuroscience.

[46]  Elly Nedivi,et al.  Inhibitory Synapses Are Repeatedly Assembled and Removed at Persistent Sites In Vivo , 2016, Neuron.

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

[48]  Javier DeFelipe,et al.  The anatomical problem posed by brain complexity and size: a potential solution , 2015, Front. Neuroanat..

[49]  H. Barbas General cortical and special prefrontal connections: principles from structure to function. , 2015, Annual review of neuroscience.

[50]  Satoru Kondo,et al.  Functional effects of distinct innervation styles of pyramidal cells by fast spiking cortical interneurons , 2015, eLife.

[51]  Nikos Makris,et al.  Large-scale brain networks of the human left temporal pole: a functional connectivity MRI study. , 2015, Cerebral cortex.

[52]  D. Nicholson,et al.  Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons , 2015, Brain Structure and Function.

[53]  M. Scanziani,et al.  Equalizing Excitation-Inhibition Ratios across Visual Cortical Neurons , 2014, Nature.

[54]  Concha Bielza,et al.  Three-Dimensional Spatial Distribution of Synapses in the Neocortex: A Dual-Beam Electron Microscopy Study , 2013, Cerebral cortex.

[55]  R. Insausti Comparative neuroanatomical parcellation of the human and nonhuman primate temporal pole , 2013, The Journal of comparative neurology.

[56]  Essa Yacoub,et al.  The WU-Minn Human Connectome Project: An overview , 2013, NeuroImage.

[57]  Rafael Yuste,et al.  Age-based comparison of human dendritic spine structure using complete three-dimensional reconstructions. , 2013, Cerebral cortex.

[58]  Jose R. Rodriguez,et al.  Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis , 2013, Frontiers in Neuroanatomy.

[59]  Thomas M. Morse,et al.  Compartmentalization of GABAergic Inhibition by Dendritic Spines , 2013, Science.

[60]  Lars A. Ross,et al.  Social cognition and the anterior temporal lobes: a review and theoretical framework. , 2013, Social cognitive and affective neuroscience.

[61]  R. Malenka,et al.  NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). , 2012, Cold Spring Harbor perspectives in biology.

[62]  Javier DeFelipe,et al.  The Evolution of the Brain, the Human Nature of Cortical Circuits, and Intellectual Creativity , 2011, Front. Neuroanat..

[63]  Javier DeFelipe,et al.  Espina: A Tool for the Automated Segmentation and Counting of Synapses in Large Stacks of Electron Microscopy Images , 2011, Front. Neuroanat..

[64]  J. DeFelipe,et al.  GABAergic complex basket formations in the human neocortex , 2010, The Journal of comparative neurology.

[65]  K. Amunts,et al.  Centenary of Brodmann's Map — Conception and Fate , 2022 .

[66]  F. Mansilla,et al.  The Human Parahippocampal Region: I. Temporal Pole Cytoarchitectonic and MRI Correlation , 2010, Cerebral cortex.

[67]  Javier DeFelipe,et al.  Counting Synapses Using FIB/SEM Microscopy: A True Revolution for Ultrastructural Volume Reconstruction , 2009, Front. Neuroanat..

[68]  Song-Lin Ding,et al.  Parcellation of human temporal polar cortex: A combined analysis of multiple cytoarchitectonic, chemoarchitectonic, and pathological markers , 2009, The Journal of comparative neurology.

[69]  J. DeFelipe,et al.  Gender differences in human cortical synaptic density , 2008, Proceedings of the National Academy of Sciences.

[70]  Karl Zilles,et al.  Cytology and receptor architecture of human anterior cingulate cortex , 2008, The Journal of comparative neurology.

[71]  A. Peters,et al.  Synapses are lost during aging in the primate prefrontal cortex , 2008, Neuroscience.

[72]  N. Spruston Pyramidal neurons: dendritic structure and synaptic integration , 2008, Nature Reviews Neuroscience.

[73]  J. DeFelipe,et al.  The distribution of chandelier cell axon terminals that express the GABA plasma membrane transporter GAT-1 in the human neocortex. , 2007, Cerebral cortex.

[74]  A. Thomson,et al.  Functional Maps of Neocortical Local Circuitry , 2007, Front. Neurosci..

[75]  J. DeFelipe,et al.  Distribution of neurons expressing tyrosine hydroxylase in the human cerebral cortex , 2007, Journal of anatomy.

[76]  R. Kötter,et al.  Mapping functional connectivity in barrel-related columns reveals layer- and cell type-specific microcircuits , 2007, Brain Structure and Function.

[77]  Olaf Sporns,et al.  The small world of the cerebral cortex , 2007, Neuroinformatics.

[78]  J. DeFelipe,et al.  Catecholaminergic innervation of pyramidal neurons in the human temporal cortex. , 2005, Cerebral cortex.

[79]  Olaf Sporns,et al.  The Human Connectome: A Structural Description of the Human Brain , 2005, PLoS Comput. Biol..

[80]  D. Nicholson,et al.  Synapses with a segmented, completely partitioned postsynaptic density express more AMPA receptors than other axospinous synaptic junctions , 2004, Neuroscience.

[81]  D. Nicholson,et al.  Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities , 2004, The Journal of comparative neurology.

[82]  Hideki Kondo,et al.  Differential connections of the temporal pole with the orbital and medial prefrontal networks in macaque monkeys , 2003, The Journal of comparative neurology.

[83]  J. DeFelipe,et al.  Microstructure of the neocortex: Comparative aspects , 2002, Journal of neurocytology.

[84]  N. Toni,et al.  Remodeling of Synaptic Membranes after Induction of Long-Term Potentiation , 2001, The Journal of Neuroscience.

[85]  R. Nicoll,et al.  Synaptic plasticity and dynamic modulation of the postsynaptic membrane , 2000, Nature Neuroscience.

[86]  J DeFelipe,et al.  Estimation of the number of synapses in the cerebral cortex: methodological considerations. , 1999, Cerebral cortex.

[87]  P. Somogyi,et al.  Salient features of synaptic organisation in the cerebral cortex 1 Published on the World Wide Web on 3 March 1998. 1 , 1998, Brain Research Reviews.

[88]  J. DeFelipe Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex , 1997, Journal of Chemical Neuroanatomy.

[89]  G. Buzsáki,et al.  Interneurons of the hippocampus , 1998, Hippocampus.

[90]  A. Damasio,et al.  A neural basis for lexical retrieval , 1996, Nature.

[91]  K. Nakamura,et al.  The primate temporal pole: its putative role in object recognition and memory , 1996, Behavioural Brain Research.

[92]  T. Freund,et al.  Differences between Somatic and Dendritic Inhibition in the Hippocampus , 1996, Neuron.

[93]  J. DeFelipe,et al.  A light and electron microscopic study of calbindin D-28k immunoreactive double bouquet cells in the human temporal cortex , 1995, Brain Research.

[94]  F. Morrell,et al.  Structural synaptic correlate of long‐term potentiation: Formation of axospinous synapses with multiple, completely partitioned transmission zones , 1993, Hippocampus.

[95]  J DeFelipe,et al.  A simple and reliable method for correlative light and electron microscopic studies. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[96]  C. Geula,et al.  Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention. , 1993, Archives of neurology.

[97]  A. Scheibel,et al.  A quantitative dendritic analysis of wernicke's area in humans. I. Lifespan changes , 1993, The Journal of comparative neurology.

[98]  A. Scheibel,et al.  A quantitative dendritic analysis of wernicke's area in humans. II. Gender, hemispheric, and environmental factors , 1993, The Journal of comparative neurology.

[99]  J. DeFelipe,et al.  The pyramidal neuron of the cerebral cortex: Morphological and chemical characteristics of the synaptic inputs , 1992, Progress in Neurobiology.

[100]  F. Morrell,et al.  Structural synaptic plasticity associated with the induction of long‐term potentiation is preserved in the dentate gyrus of aged rats , 1992, Hippocampus.

[101]  M. Cynader,et al.  Quantitative distribution of GABA-immunopositive and -immunonegative neurons and synapses in the monkey striate cortex (area 17). , 1992, Cerebral cortex.

[102]  F. Morrell,et al.  Increase in the number of axospinous synapses with segmented postsynaptic densities following hippocampal kindling , 1992, Brain Research.

[103]  D. Peterson,et al.  Neurite growth from, and neuronal survival within, cultured explants of the nervous system: A critical review of morphometric and stereological methods, and suggestions for the future , 1991, Progress in Neurobiology.

[104]  Leyla deToledo-Morrell,et al.  Induction of long-term potentiation is associated with an increase in the number of axospinous synapses with segmented postsynaptic densities , 1991, Brain Research.

[105]  D. J. Felleman,et al.  Distributed hierarchical processing in the primate cerebral cortex. , 1991, Cerebral cortex.

[106]  E. G. Jones,et al.  A microcolumnar structure of monkey cerebral cortex revealed by immunocytochemical studies of double bouquet cell axons , 1990, Neuroscience.

[107]  A. Damasio,et al.  Face agnosia and the neural substrates of memory. , 1990, Annual review of neuroscience.

[108]  E. G. Jones,et al.  Synapses of double bouquet cells in monkey cerebral cortex visualized by calbindin immunoreactivity , 1989, Brain Research.

[109]  J. Morrison,et al.  Ultrastructural analysis of somatostatin‐immunoreactive neurons and synapses in the temporal and occipital cortex of the macaque monkey , 1989, The Journal of comparative neurology.

[110]  H. J. G. GUNDERSEN,et al.  Some new, simple and efficient stereological methods and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[111]  F. Morrell,et al.  Axospinous synapses with segmented postsynaptic densities: a morphologically distinct synaptic subtype contributing to the number of profiles of ‘perforated’ synapses visualized in random sections , 1987, Brain Research.

[112]  M. Mesulam,et al.  Neural inputs into the temporopolar cortex of the rhesus monkey , 1987, The Journal of comparative neurology.

[113]  A. Cowey,et al.  Combined golgi and electron microscopic study on the synapses formed by double bouquet cells in the visual cortex of the cat and monkey , 1981, The Journal of comparative neurology.

[114]  E. Gray,et al.  Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron microscope study. , 1959, Journal of anatomy.

[115]  J. R.,et al.  Quantitative analysis , 1892, Nature.