Hierarchical Organization of Neocortical Neuron Types



The neocortex consists of many diverse neuron populations distributed across cortical layers having specialized connectivity and projection patterns. Glutamatergic pyramidal cells, which are cortical projection neurons, reside in all layers except layer 1, while GABAergic nonpyramidal cells are ubiquitous throughout all cortical layers. These broad classes of excitatory and inhibitory neurons comprise specialized neuron subtypes that have specific morphological, physiological, and chemical properties. However, while much is now known about the types in the cortex, less is known regarding the rules governing their selective connectivity into cortical and extracortical circuits. In layer 5 of the rat frontal cortex, several distinct populations of pyramidal cells are identifiable based on their distinct extracortical projections, firing characteristics, morphologies, and positions within layer 5. We have characterized highly selective synaptic connectivity among and between these pyramidal cell populations, which likely contributes to their establishing and maintaining functional loops between the frontal cortex, basal ganglia, and thalamus. However, less is known about how GABAergic neuron subpopulations are selectively incorporated into cortical circuits or how they might differentially regulate cortical output to subcortical targets.


Pyramidal Cell Vasoactive Intestinal Polypeptide Perirhinal Cortex Reward Prediction Error Ipsilateral Striatum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author thanks Drs. Allan T. Gulledge, Yasuharu Hirai, Yoshiyuki Kubota, Kenji Morita, Mieko Morishima, and Takeshi Otsuka for their collaboration and discussion. This work was supported by JST, CREST, and Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT).


  1. Barth AL, Poulet JF (2012) Experimental evidence for sparse firing in the neocortex. Trends Neurosci 35:345–355PubMedCrossRefGoogle Scholar
  2. Burwell RD, Amaral DG (1998) Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J Comp Neurol 398:179–205PubMedCrossRefGoogle Scholar
  3. Cenquizca LA, Swanson LW (2006) Analysis of direct hippocampal cortical field CA1 axonal projections to diencephalon in the rat. J Comp Neurol 497:101–114PubMedCrossRefGoogle Scholar
  4. Cenquizca LA, Swanson LW (2007) Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex. Brain Res Rev 56:1–26PubMedCrossRefGoogle Scholar
  5. Clark AM, Bouret S, Young AM, Richmond BJ (2012) Intersection of reward and memory in monkey rhinal cortex. J Neurosci 32:6869–6877PubMedCrossRefGoogle Scholar
  6. DeFelipe J, Fariñas I (1992) The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog Neurobiol 39:563–607PubMedCrossRefGoogle Scholar
  7. Descarries L, Gisiger V, Steriade M (1997) Diffuse transmission by acetylcholine in the CNS. Prog Neurobiol 53:603–625PubMedCrossRefGoogle Scholar
  8. Doya K (1999) What are the computations of the cerebellum, the basal ganglia and the cerebral cortex? Neural Netw 12:961–974PubMedCrossRefGoogle Scholar
  9. Eichenbaum H (2006) Remembering: functional organization of the declarative memory system. Curr Biol 16:R643–R645PubMedCrossRefGoogle Scholar
  10. Fino E, Packer AM, Yuste R (2012) The logic of inhibitory connectivity in the neocortex. Neuroscientist. doi: 10.1177/1073858412456743 PubMedGoogle Scholar
  11. Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol 492:145–177PubMedCrossRefGoogle Scholar
  12. Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466PubMedCrossRefGoogle Scholar
  13. Glimcher PW (2011) Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis. Proc Natl Acad Sci U S A 108(Suppl 3):15647–15654PubMedCrossRefGoogle Scholar
  14. Gulledge AT, Kawaguchi Y (2007) Phasic cholinergic signaling in the hippocampus: functional homology with the neocortex? Hippocampus 17:327–332PubMedCrossRefGoogle Scholar
  15. Gulledge AT, Stuart GJ (2005) Cholinergic inhibition of neocortical pyramidal neurons. J Neurosci 25:10308–10320PubMedCrossRefGoogle Scholar
  16. Gulledge AT, Park SB, Kawaguchi Y, Stuart GJ (2007) Heterogeneity of phasic cholinergic signaling in neocortical neurons. J Neurophysiol 97:2215–2229PubMedCrossRefGoogle Scholar
  17. Hattox AM, Nelson SB (2007) Layer V neurons in mouse cortex projecting to different targets have distinct physiological properties. J Neurophysiol 98:3330–3340PubMedCrossRefGoogle Scholar
  18. Hirai Y, Morishima M, Karube F, Kawaguchi Y (2012) Specialized cortical subnetworks differentially connect frontal cortex to parahippocampal areas. J Neurosci 32:1898–1913PubMedCrossRefGoogle Scholar
  19. Houk JC (2010) Voluntary movement: control, learning and memory. In: Encyclopedia of behavioral neuroscience. Academic, Oxford, pp 455–458CrossRefGoogle Scholar
  20. Jones EG (1984) Laminar distribution of output cells. In: Peters A, Jones EG (eds) Cellular components of the cerebral cortex, vol 1, Cerebral cortex. Plenum, New York, pp 521–553CrossRefGoogle Scholar
  21. Jones EG (2001) The thalamic matrix and thalamocortical synchrony. Trends Neurosci 24:595–601PubMedCrossRefGoogle Scholar
  22. Karube F, Kubota Y, Kawaguchi Y (2004) Axon branching and synaptic bouton phenotypes in GABAergic nonpyramidal cell subtypes. J Neurosci 24:2853–2865PubMedCrossRefGoogle Scholar
  23. Kasper EM, Larkman AU, Lübke J, Blakemore C (1994) Pyramidal neurons in layer 5 of the rat visual cortex. I. Correlation among cell morphology, intrinsic electrophysiological properties, and axon targets. J Comp Neurol 339:459–474PubMedCrossRefGoogle Scholar
  24. Kawaguchi Y, Karube F (2008) Structures and circuits: cerebral cortex, inhibitory cells. In: Squire L (ed) The new encyclopedia of neuroscience. Elsevier, OxfordGoogle Scholar
  25. Kawaguchi Y, Kondo S (2002) Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex. J Neurocytol 31:277–287PubMedCrossRefGoogle Scholar
  26. Kawaguchi Y, Karube F, Kubota Y (2006) Dendritic branch typing and spine expression patterns in cortical nonpyramidal cells. Cereb Cortex 16:696–711PubMedCrossRefGoogle Scholar
  27. Kita T, Kita H (2012) The subthalamic nucleus is one of multiple innervation sites for long-range corticofugal axons: a single-axon tracing study in the rat. J Neurosci 32:5990–5999PubMedCrossRefGoogle Scholar
  28. Kubota Y, Hatada S, Kondo S, Karube F, Kawaguchi Y (2007) Neocortical inhibitory terminals innervate dendritic spines targeted by thalamocortical afferents. J Neurosci 27:1139–1150PubMedCrossRefGoogle Scholar
  29. Kubota Y, Karube F, Nomura M, Gulledge AT, Mochizuki A, Schertel A, Kawaguchi Y (2011a) Conserved properties of dendritic trees in four cortical interneuron subtypes. Sci Rep 1:89PubMedCrossRefGoogle Scholar
  30. Kubota Y, Shigematsu N, Karube F, Sekigawa A, Kato S, Yamaguchi N, Hirai Y, Morishima M, Kawaguchi Y (2011b) Selective coexpression of multiple chemical markers defines discrete populations of neocortical GABAergic neurons. Cereb Cortex 21:1803–1817PubMedCrossRefGoogle Scholar
  31. Kuramoto E, Furuta T, Nakamura KC, Unzai T, Hioki H, Kaneko T (2009) Two types of thalamocortical projections from the motor thalamic nuclei of the rat: a single neuron-tracing study using viral vectors. Cereb Cortex 19:2065–2077PubMedCrossRefGoogle Scholar
  32. Lei W, Jiao Y, Del Mar N, Reiner A (2004) Evidence for differential cortical input to direct pathway versus indirect pathway striatal projection neurons in rats. J Neurosci 24:8289–8299PubMedCrossRefGoogle Scholar
  33. Markram H, Lübke J, Frotscher M, Roth A, Sakmann B (1997) Physiology and anatomy of synaptic connections between thick tufted pyramidal neurons in the developing rat neocortex. J Physiol 500:409–440PubMedGoogle Scholar
  34. Markram H, Wang Y, Tsodyks M (1998) Differential signaling via the same axon of neocortical pyramidal neurons. Proc Natl Acad Sci U S A 95:5323–5328PubMedCrossRefGoogle Scholar
  35. Miyashita Y (2004) Cognitive memory: cellular and network machineries and their top-down control. Science 306:435–440PubMedCrossRefGoogle Scholar
  36. Morishima M, Kawaguchi Y (2006) Recurrent connection patterns of corticostriatal pyramidal cells in frontal cortex. J Neurosci 26:4394–4405PubMedCrossRefGoogle Scholar
  37. Morishima M, Morita K, Kubota Y, Kawaguchi Y (2011) Highly differentiated projection-specific cortical subnetworks. J Neurosci 31:10380–10391PubMedCrossRefGoogle Scholar
  38. Morita K, Morishima M, Sakai K, Kawaguchi Y (2012) Reinforcement learning: computing the temporal difference of values via distinct corticostriatal pathways. Trends Neurosci 35:457–467PubMedCrossRefGoogle Scholar
  39. Otsuka T, Kawaguchi Y (2008) Firing-pattern-dependent specificity of cortical excitatory feed-forward subnetworks. J Neurosci 28:11186–11195PubMedCrossRefGoogle Scholar
  40. Otsuka T, Kawaguchi Y (2009) Cortical inhibitory cell types differentially form intralaminar and interlaminar subnetworks with excitatory neurons. J Neurosci 29:10533–10540PubMedCrossRefGoogle Scholar
  41. Otsuka T, Kawaguchi Y (2011) Cell diversity and connection specificity between callosal projection neurons in the frontal cortex. J Neurosci 31:3862–3870PubMedCrossRefGoogle Scholar
  42. Peters A, Jones EG (1984) Classification of cortical neurons. In: Peters A, Jones EG (eds) Cellular components of the cerebral cortex, vol 1, Cerebral cortex. Plenum, New York, pp 107–121Google Scholar
  43. Reiner A, Hart NM, Lei W, Deng Y (2010) Corticostriatal projection neurons – dichotomous types and dichotomous functions. Front Neuroanat 4:142PubMedCrossRefGoogle Scholar
  44. Rockland KS (1997) Elements of cortical architecture: hierarchy revisited. In: Rockland KS, Kaas JH, Peters A (eds) Extrastriate cortex in primates, vol 12, Cerebral cortex. Plenum, New York, pp 243–293CrossRefGoogle Scholar
  45. Rubio-Garrido P, Pérez-de-Manzo F, Porrero C, Galazo MJ, Clascá F (2009) Thalamic input to distal apical dendrites in neocortical layer 1 is massive and highly convergent. Cereb Cortex 19:2380–2395PubMedCrossRefGoogle Scholar
  46. Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599PubMedCrossRefGoogle Scholar
  47. Scimeca JM, Badre D (2012) Striatal contributions to declarative memory retrieval. Neuron 75:380–392PubMedCrossRefGoogle Scholar
  48. Thomson AM (2010) Neocortical layer 6, a review. Front Neuroanat 4:13PubMedGoogle Scholar
  49. Thomson AM, Bannister AP (2003) Interlaminar connections in the neocortex. Cereb Cortex 13:5–14PubMedCrossRefGoogle Scholar
  50. Uematsu M, Hirai Y, Karube F, Ebihara S, Kato M, Abe K, Obata K, Yoshida S, Hirabayashi M, Yanagawa Y, Kawaguchi Y (2008) Quantitative chemical composition of cortical GABAergic neurons revealed in transgenic Venus-expressing rats. Cereb Cortex 18:315–330PubMedCrossRefGoogle Scholar
  51. Ueta Y, Otsuka T, Morishima M, Ushimaru M, Kawaguchi Y (2013) Multiple layer 5 pyramidal cell subtypes relay cortical feedback from secondary to primary motor areas in rats. Cereb Cortex. doi: 10.1093/cercor/bht088
  52. Veinante P, Deschênes M (2003) Single-cell study of motor cortex projections to the barrel field in rats. J Comp Neurol 464:98–103PubMedCrossRefGoogle Scholar
  53. Wang XJ (2001) Synaptic reverberation underlying mnemonic persistent activity. Trends Neurosci 24:455–463PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  1. 1.Division of Cerebral Circuitry, Department of Physiological Sciences, National Institute for Physiological SciencesGraduate University for Advanced Studies (SOKENDAI)OkazakiJapan
  2. 2.JST, CRESTTokyoJapan

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