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Pharmacopsychiatry 2006; 39: 80-87
DOI: 10.1055/s-2006-931501
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Toward a Prefrontal Microcircuit Model for Cognitive Deficits in Schizophrenia

X.-J. Wang1
  • 1Volen Center for Complex Systems, Brandeis University, Waltham, USA
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Publication History

Publication Date:
01 March 2006 (online)

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I present here a biophysically-based model of cortical microcircuits capable of both internal representation (memory storage) and dynamical processing (decision and action selection). The model is illustrated through computer simulations that account for neurophysiological and behavioral data from studies using nonhuman primates. This computational theory proposes that an interplay between slow reverberating excitation and competitive synaptic inhibition enables a cortical area, such as the prefrontal cortex, to subserve cognitive functions. It is argued that quantitatively accurate microcircuit models can potentially provide a framework for a systematic approach to pharmacological treatment of schizophrenia and other mental disorders.

References

  • 1 Abbott L F, Regehr W G. Synaptic computation.  Nature. 2004;  431 796-803.
    CrossrefPubMedGoogle Scholar
  • 2 Akbarian S, Sucher N J, Bradley D, Tazzofoli A, Trinh D, Hetrick W P, Potkin S G, Sandman C A, Bunney W , Jones E G. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics.  J Neurosci. 1996;  16 19-30.
    PubMedGoogle Scholar
  • 3 Amari S. Dynamics of pattern formation in lateral-inhibition type neural fields.  Biol Cybern. 1977;  27 77-87
    CrossrefPubMedGoogle Scholar
  • 4 Amit D J. The Hebbian paradigm reintegrated: local reverberations as internal representations.  Behav Brain Sci. 1995;  18 617-626
    PubMedGoogle Scholar
  • 5 Amit D J, Brunel N. Model of global spontaneous activity and local structured activity during delay periods in the cerebral cortex.  Cerebral Cortex. 1995;  7 237-252
    PubMedGoogle Scholar
  • 6 Brederode J FV, Mulligan K A, Hendrickson A E. Calciumbinding proteins as markers for subpopulations of GABAergic neurons in monkey striate cortex.  J Comp Neurol. 1990;  298 1-22
    PubMedGoogle Scholar
  • 7 Brunel N, Wang X -J. Effects of neuromodulation in a cortical network model of object working memory dominated by recurrent inhibition.  J Comput Neurosci. 2001;  11 63-85
    CrossrefPubMedGoogle Scholar
  • 8 Camperi M, Wang X -J. A model of visuospatial short-term memory in prefrontal cortex: recurrent network and cellular bistability.  J Comput. Neurosci1998;  5 383-405
    PubMedGoogle Scholar
  • 9 Chen G, Greengard P, Yan Z. Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex.  Proc Natl Acad Sci U S A. 2004;  101 2596-2600
    CrossrefPubMedGoogle Scholar
  • 10 Compte A, Brunel N, Goldman-Rakic P S, Wang X -J. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model.  Cereb Cortex. 2000;  10 910-923
    CrossrefPubMedGoogle Scholar
  • 11 Conde F, Lund J S, Jacobowitz D M, Baimbridge K G, Lewis D A. Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: distribution and morphology.  J Comp Neurol. 1994;  341 95-116
    PubMedGoogle Scholar
  • 12 Constantinidis C, Goldman-Rakic P S. Correlated discharges among putative pyramidal neurons and interneurons in the primate prefrontal cortex.  J Neurophysiol. 2002;  88 3487-3497
    PubMedGoogle Scholar
  • 13 Constantinidis C, Procyk E. The primate working memory networks.  Cogn Affect Behav Neurosci. 2004;  444-465
    PubMedGoogle Scholar
  • 14 Constantinidis C, Wang X -J. A neural circuit basis for spatial working memory.  Neuroscientist. 2004;  10 553-565
    CrossrefPubMedGoogle Scholar
  • 15 Coyle J T, Tsai G, Goff D. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia.  Ann N Y Acad Sci. 2003;  1003 318-327
    CrossrefPubMedGoogle Scholar
  • 16 Curtis CE,D’Esposito M. Persistent activity in the prefrontal cortex during working memory.  Trends Cogn Sci. 2003;  7 415-423
    CrossrefPubMedGoogle Scholar
  • 17 Douglas R J, Martin K AC. Neuronal circuits of the neocortex.  Annu Rev Neurosci. 2004;  27 419-451
    CrossrefPubMedGoogle Scholar
  • 18 Durstewitz D, Seamans J K, Sejnowski T J. Neurocomputational models of working memory.  Nature Neurosci. 2000;  3 1184-1191
    CrossrefPubMedGoogle Scholar
  • 19 Egorov A V, Hamam B N, Fransen E, Hasselmo M E, Alonso A A. Graded persistent activity in entorhinal cortex neurons.  Nature. 2002, Nov;  420 (6912) 173-178
    PubMedGoogle Scholar
  • 20 Funahashi S, Bruce C J, Goldman-Rakic P S. Mnemonic coding of visual space in the monkey’s dorsolateral prefrontal cortex.  J Neurophysiol. 1989;  61 331-349
    PubMedGoogle Scholar
  • 21 Fuster J M. The Prefrontal Cortex (2nd ed.) New York; Raven 1988
    Google Scholar
  • 22 Fuster J M, Alexander G. Neuron activity related to short-term memory.  Science. 1971;  173 652-654
    CrossrefPubMedGoogle Scholar
  • 23 Gabbott P LA, Bacon S J. Local circuit neurons in the medial prefrontal cortex (areas 24a,b,c, 25 and 32) in the monkey: II. Quantitative areal and laminar distributions.  J Comp Neurol. 1996;  364 609-636
    PubMedGoogle Scholar
  • 24 Gao W -J, Wang Y, Goldman-Rakic P S. Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex.  J Neurosci. 2003;  23 1622-1630
    PubMedGoogle Scholar
  • 25 Goldman M S, Levine J H, Major G, Tank D W, Seung H S. Robust persistent neural activity in a model integrator with multiple hysteretic dendrites per neuron.  Cereb Cortex. 2003;  13 1185-1195
    CrossrefPubMedGoogle Scholar
  • 26 Goldman-Rakic P S. Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In Handbook of Physiology - The nervous system V, Chapter 9. pp. 373-417 Bethesda, Maryland; American Physiological Society 1987
    Google Scholar
  • 27 Goldman-Rakic P S. Working memory dysfunction in schizophrenia.  J Neuropsych and Clin Neurosci. 1994;  6 348-357
    PubMedGoogle Scholar
  • 28 Goldman-Rakic P S. Cellular basis of working memory.  Neuron. 1995;  14 477-485
    CrossrefPubMedGoogle Scholar
  • 29 Harrison P J, Weinberger D R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.  Mol Psychiatry. 2005;  10 40-68
    CrossrefPubMedGoogle Scholar
  • 30 Hebb D O. Organization of behavior. New York; Wiley 1949
    Google Scholar
  • 31 Huang Y -Y, Simpson E, Kellendonk C, Kandel E R. Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors.  Proc Natl Acad Sci U S A. 2004;  101 3236-3241
    CrossrefPubMedGoogle Scholar
  • 32 Jacobsen C F. Studies of cerebral function in primates: I. the functions of the frontal association areas in monkeys.  Comp Psychol Monogr. 1936;  13 1-68
    PubMedGoogle Scholar
  • 33 Koulakov A A, Raghavachari S, Kepecs A, Lisman J E. Model for a robust neural integrator.  Nat Neurosci. 2002;  5 775-782
    CrossrefPubMedGoogle Scholar
  • 34 Kritzer M F, Goldman-Rakic P S. Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the rhesus monkey.  J Comp Neurol. 1995;  359 131-143
    PubMedGoogle Scholar
  • 35 Krystal J H, Karper L P, Seibyl J P, Freeman G K, Delaney R, Bremner J D, Heninger G R, Bowers M B, Charney D S. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. psychotomimetic, perceptual, cognitive, and neuroendocrine responses.  Arch Gen Psychiatry. 1994;  51 199-214
    CrossrefPubMedGoogle Scholar
  • 36 Lee K -H, Williams L M, Breakspear M, Gordon E. Synchronous gamma activity: a review and contribution to an integrative neuroscience model of schizophrenia.  Brain Res Brain Res Rev. 2003;  41 57-78
    CrossrefPubMedGoogle Scholar
  • 37 Levitt B, Lewis D A, Yoshioka T, Lund J. Topography of pyramidal neuron intrinsic connections in macaque monkey prefrontal cortex (areas 9 and 46).  J Comp Neurol. 1993;  338  360-376
    PubMedGoogle Scholar
  • 38 Lewis D A, Hashimoto T, Volk D W. Cortical inhibitory neurons and schizophrenia.  Nat Rev Neurosci. 2005;  6 312-324
    CrossrefPubMedGoogle Scholar
  • 39 Lisman J E, Fellous JM,Wang X J. A role for NMDA-receptor channels in working memory.  Nat Neurosci. 1998;  1 273-275
    CrossrefPubMedGoogle Scholar
  • 40 Llinas R R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function.  Science. 1988;  242 1654-1664
    CrossrefPubMedGoogle Scholar
  • 41 Loewenstein Y, Sompolinsky H. Temporal integration by calcium dynamics in a model neuron.  Nat Neurosci. 2003;  6 961-967
    CrossrefPubMedGoogle Scholar
  • 42 Lorente de N'o R. Vestibulo-ocular reflex arc.  Arch Neurol Psych. 1993;  30 245-291
    PubMedGoogle Scholar
  • 43 Machens C K, Romo R, Brody C D. Flexible control of mutual inhibition: a neural model of two-interval discrimination.  Science. 2005;  307 1121-1124
    CrossrefPubMedGoogle Scholar
  • 44 Magee J, Hoffman D, Colbert C, Johnston D. Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons.  Annu Rev Physiol. 1998;  60 327-346
    CrossrefPubMedGoogle Scholar
  • 45 Major G, Tank D. Persistent neural activity: prevalence and mechisms.  Curr Opin Neurobiol. 2004;  14 675-684
    CrossrefPubMedGoogle Scholar
  • 46 Markram H, Gupta A, Uziel A, Wang Y, Tsodyks M. Information processing with frequency-dependent synaptic connections.  Neurobiol Learn Mem. 1998;  70 101-112
    CrossrefPubMedGoogle Scholar
  • 47 Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system.  Nat Rev Neurosci. 2004;  5 793-807
    CrossrefPubMedGoogle Scholar
  • 48 Meskenaite V. Calretinin-immunoreactive local circuit neurons in the area 17 of the cynomolgus monkey, Macaca fascicularis.  J Comp Neurol. 1997;  379  113-132
    PubMedGoogle Scholar
  • 49 Mesulam M -M. Principles of behavioral and cognitive neurology (2nd ed.) New York; Oxford University Press 2000
    Google Scholar
  • 50 Miller E K, Cohen J D. An integrative theory of prefrontal cortex function.  Annu Rev Neurosci. 2001;  24 167-202
    Google Scholar
  • 51 Miller E K, Erickson C A, Desimone R. Neural mechanisms of visual working memory in prefrontal cortex of the macaque.  J Neurosci. 1996;  16 5154-5167
    PubMedGoogle Scholar
  • 52 Miller P, Brody C D, Romo R, Wang X J. A recurrent network model of somatosensory parametric working memory in the prefrontal cortex.  Cereb Cortex. 2003;  13 1208-1218
    CrossrefPubMedGoogle Scholar
  • 53 Miller P, Wang X -J. Inhibitory control by an integral feedback signal in prefrontal cortex: a model of discrimination between sequential stimuli.  Proc Natl Acad Sci (USA). 2006;  103(1) 201-206
    CrossrefPubMedGoogle Scholar
  • 54 Powell K D, Goldberg M E. Response of neurons in the lateral intraparietal area to a distractor flashed during the delay period of a memoryguided saccade.  J Neurophysiol. 2000;  84 301-310
    PubMedGoogle Scholar
  • 55 Rainer G, Assad W F, Miller E K. Memory fields of neurons in the primate prefrontal cortex.  Proc Natl Acad Sci (USA). 1998;  95 15 008-15 013
    PubMedGoogle Scholar
  • 56 Rao S G, Williams G V, Goldman-Rakic P S. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory.  J Neurosci. 2000;  20 485-494
    PubMedGoogle Scholar
  • 57 Renart A, Brunel N, Wang X -J. Mean-field theory of recurrent cortical networks: Working memory circuits with irregularly spiking neurons. In J. Feng (Ed.) Computational Neuroscience: A Comprehensive Approach. Boca Raton; CRC Press 2003
    Google Scholar
  • 58 Renart A, Song P, Wang X J. Robust spatial working memory through homeostatic synaptic scaling in heterogeneous cortical networks.  Neuron. 2003;  38 473-485
    CrossrefPubMedGoogle Scholar
  • 59 Romo R, Brody C D, Hernandez A, Lemus L. Neuronal correlates of parametric working memory in the prefrontal cortex.  Nature. 1999;  399 470-473
    PubMedGoogle Scholar
  • 60 Scherzer C R, Landwehrmeyer G B, Kerner J A, Counihan T J, Kosinski C M, Standaert D G, Daggett L P, Velicelebi G, Penney J B, Young A B. Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: hippocampus and cortex.  J Comp Neurol. 1998;  390  75-90
    PubMedGoogle Scholar
  • 61 Seamans J K, Yang C R. The principal features and mechanisms of dopamine modulation in the prefrontal cortex.  Prog Neurobiol. 2004;  74 1-58
    CrossrefPubMedGoogle Scholar
  • 62 Seung H S, Lee D D, Reis B Y, Tank D W. Stability of the memory of eye position in a recurrent network of conductance-based model neurons.  Neuron. 2000;  26 259-271
    CrossrefPubMedGoogle Scholar
  • 63 Somogyi P, Tamas G, Lujan R, Buhl E H. Salient features of synaptic organisation in the cerebral cortex.  Brain Res Rev. 1998;  26 113-135
    CrossrefPubMedGoogle Scholar
  • 64 Spencer K M, Nestor P G, Perlmutter R, Niznikiewicz M A, Klump M C, Frumin M, Shenton M E, McCarley R W. Neural synchrony indexes disordered perception and cognition in schizophrenia.  Proc Natl Acad Sci U S A. 2004;  101 17 288-17 293
    PubMedGoogle Scholar
  • 65 Stuss D T, Knight R T. Principles of frontal lobe function. New York; Oxford University Press 2002
    Google Scholar
  • 66 TegnŽer J, Compte A, Wang X -J. Dynamical stability of reverberatory neural circuits.  Biol Cybern. 2002;  87 471-481
    CrossrefPubMedGoogle Scholar
  • 67 Wang X -J. Synaptic basis of cortical persistent activity: the importance of NMDA receptors to working memory.  J Neurosci. 1999;  19 9587-9603
    PubMedGoogle Scholar
  • 68 Wang X -J. Synaptic reverberation underlying mnemonic persistent activity.  Trends in Neurosci. 2001;  24 455-463
    CrossrefPubMedGoogle Scholar
  • 69 Wang X -J. Probabilistic decision making by slow reverberation in cortical circuits.  Neuron. 2002;  36  955-968
    CrossrefPubMedGoogle Scholar
  • 70 Wang X -J. A microcircuit model of prefrontal functions: ying and yang of reverberatory neurodynamics in cognition.  In The Prefrontal Lobes: Development, Function and Pathology. New York; Cambridge University Press 2006
    Google Scholar
  • 71 Wang X -J, Goldman-Rakic P S (eds.). Special issue: Persistent neural activity: theory and experiments.  Cerebral Cortex. 2003;  13 1123-1269
    CrossrefPubMedGoogle Scholar
  • 72 Wang X -J, Tegner J, Constantinidis C, Goldman-Rakic P S. Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.  Proc Natl Acad Sci U S A. 2004;  101 1368-1373
    CrossrefPubMedGoogle Scholar
  • 73 Weinberger D R, Berman K F. Prefrontal function in schizophrenia: confounds and controversies.  Phil Trans R Soc Lond B. 1996;  351 1495-1503
    PubMedGoogle Scholar
  • 74 Wilson H R, Cowan J D. A mathematical theory of the functional dynamics of cortical and thalamic nervous tissue.  Kybernetik. 1973;  13 55-80
    CrossrefPubMedGoogle Scholar
  • 75 Wood J N, Grafman J. Human prefrontal cortex: processing and representational perspectives.  Nat Rev Neurosci. 2003;  4 139-147
    CrossrefPubMedGoogle Scholar

Xiao-Jing Wang

Volen Center for Complex Systems, MS 013, Brandeis University

415 South Street

Waltham, MA 02254-9110

USA

Phone: (781) 736 3147

Fax: (781) 736 2915

Email: xjwang@brandeis.edu

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