Toward a Prefrontal Microcircuit Model for Cognitive Deficits in Schizophrenia

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.
• 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.
• 3 Amari S. Dynamics of pattern formation in lateral-inhibition type neural fields.  Biol Cybern. 1977;  27 77-87
• 4 Amit D J. The Hebbian paradigm reintegrated: local reverberations as internal representations.  Behav Brain Sci. 1995;  18 617-626
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 13 Constantinidis C, Procyk E. The primate working memory networks.  Cogn Affect Behav Neurosci. 2004;  444-465
• 14 Constantinidis C, Wang X -J. A neural circuit basis for spatial working memory.  Neuroscientist. 2004;  10 553-565
• 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
• 16 Curtis CE,D’Esposito M. Persistent activity in the prefrontal cortex during working memory.  Trends Cogn Sci. 2003;  7 415-423
• 17 Douglas R J, Martin K AC. Neuronal circuits of the neocortex.  Annu Rev Neurosci. 2004;  27 419-451
• 18 Durstewitz D, Seamans J K, Sejnowski T J. Neurocomputational models of working memory.  Nature Neurosci. 2000;  3 1184-1191
• 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
• 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
• 21 Fuster J M. The Prefrontal Cortex (2nd ed.) New York; Raven 1988
• 22 Fuster J M, Alexander G. Neuron activity related to short-term memory.  Science. 1971;  173 652-654
• 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
• 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
• 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
• 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
• 27 Goldman-Rakic P S. Working memory dysfunction in schizophrenia.  J Neuropsych and Clin Neurosci. 1994;  6 348-357
• 28 Goldman-Rakic P S. Cellular basis of working memory.  Neuron. 1995;  14 477-485
• 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
• 30 Hebb D O. Organization of behavior. New York; Wiley 1949
• 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
• 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
• 33 Koulakov A A, Raghavachari S, Kepecs A, Lisman J E. Model for a robust neural integrator.  Nat Neurosci. 2002;  5 775-782
• 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
• 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
• 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
• 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
• 38 Lewis D A, Hashimoto T, Volk D W. Cortical inhibitory neurons and schizophrenia.  Nat Rev Neurosci. 2005;  6 312-324
• 39 Lisman J E, Fellous JM,Wang X J. A role for NMDA-receptor channels in working memory.  Nat Neurosci. 1998;  1 273-275
• 40 Llinas R R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function.  Science. 1988;  242 1654-1664
• 41 Loewenstein Y, Sompolinsky H. Temporal integration by calcium dynamics in a model neuron.  Nat Neurosci. 2003;  6 961-967
• 42 Lorente de N'o R. Vestibulo-ocular reflex arc.  Arch Neurol Psych. 1993;  30 245-291
• 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
• 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
• 45 Major G, Tank D. Persistent neural activity: prevalence and mechisms.  Curr Opin Neurobiol. 2004;  14 675-684
• 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
• 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
• 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
• 49 Mesulam M -M. Principles of behavioral and cognitive neurology (2nd ed.) New York; Oxford University Press 2000
• 50 Miller E K, Cohen J D. An integrative theory of prefrontal cortex function.  Annu Rev Neurosci. 2001;  24 167-202
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 65 Stuss D T, Knight R T. Principles of frontal lobe function. New York; Oxford University Press 2002
• 66 TegnŽer J, Compte A, Wang X -J. Dynamical stability of reverberatory neural circuits.  Biol Cybern. 2002;  87 471-481
• 67 Wang X -J. Synaptic basis of cortical persistent activity: the importance of NMDA receptors to working memory.  J Neurosci. 1999;  19 9587-9603
• 68 Wang X -J. Synaptic reverberation underlying mnemonic persistent activity.  Trends in Neurosci. 2001;  24 455-463
• 69 Wang X -J. Probabilistic decision making by slow reverberation in cortical circuits.  Neuron. 2002;  36  955-968
• 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
• 71 Wang X -J, Goldman-Rakic P S (eds.). Special issue: Persistent neural activity: theory and experiments.  Cerebral Cortex. 2003;  13 1123-1269
• 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
• 73 Weinberger D R, Berman K F. Prefrontal function in schizophrenia: confounds and controversies.  Phil Trans R Soc Lond B. 1996;  351 1495-1503
• 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
• 75 Wood J N, Grafman J. Human prefrontal cortex: processing and representational perspectives.  Nat Rev Neurosci. 2003;  4 139-147