The maintenance of a mental image in memory over a time scale of seconds is mediated by the persistent discharges of neurons in a distributed brain network. The representation of the spatial location of a remembered visual stimulus has been studied most extensively and provides the best-understood model of how mnemonic information is encoded in the brain. Neural correlates of spatial working memory are manifested in multiple brain areas, including the prefrontal and parietal association cortices. Spatial working memory ability is severely compromised in schizophrenia, a condition that has been linked to prefrontal cortical malfunction. Recent computational modeling work, in interplay with physiological studies of behaving monkeys, has begun to identify microcircuit properties and neural dynamics that are sufficient to generate memory-related persistent activity in a recurrent network of excitatory and inhibitory neurons during spatial working memory. This review summarizes recent results and discusses issues of current debate. It is argued that understanding collective neural dynamics in a recurrent microcircuit provides a key step in bridging the gap between network memory function and its underlying cellular mechanisms. Progress in this direction will shed fundamental insights into the neural basis of spatial working memory impairment associated with mental disorders.
Andersen RA, Essick GK, Siegel RM. 1987. Neurons of area 7 activated by both visual stimuli and oculomotor behavior. Exp Brain Res67:316-322.
2.
Asaad WF, Rainer G, Miller EK. 1998. Neural activity in the primate prefrontal cortex during associative learning. Neuron21:1399-1407.
3.
Asaad WF, Rainer G, Miller EK. 2000. Task-specific neural activity in the primate prefrontal cortex. J Neurophysiol84:451-459.
4.
Azuma M, Suzuki H.1984. Properties and distribution of auditory neurons in the dorsolateral prefrontal cortex of the alert monkey. Brain Res298:343-346.
5.
Baddeley A.1992. Working memory. Science255:556-559.
6.
Baeg EH, Kim YB, Huh K, Mook-Jung I, Kim HT, Jung MW. 2003. Dynamics of population code for working memory in the pre-frontal cortex. Neuron40:177-188.
7.
Bisley JW, Zaksas D, Droll J, Pasternak T.2004. Activity of neurons in cortical area MT during a memory for motion task. J Neurophysiol91:286-300.
8.
Bodner M, Kroger J, Fuster JM. 1996. Auditory memory cells in dorsolateral prefrontal cortex. Neuroreport7:1905-1908.
9.
Brunel N, Wang XJ. 2001. Effects of neuromodulation in a cortical network model of object working memory dominated by recurrent inhibition. J Comput Neurosci11:63-85.
10.
Brunel N, Wang XJ. 2003. What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance. J Neurophysiol90:415-430.
11.
Bunge SA, Ochsner KN, Desmond JE, Glover GH, Gabrieli JD. 2001. Prefrontal regions involved in keeping information in and out of mind. Brain124:2074-2086.
12.
Camperi M, Wang XJ. 1998. A model of visuospatial working memory in prefrontal cortex: recurrent network and cellular bistability. J Comput Neurosci5:383-405.
13.
Carter CS, Robertson LC, Nordahl TE, Kraft L, Chaderjian M, Oshora-Celaya L.1996. Spatial working memory deficits and their relationship to negative symptoms in unmedicated schizophrenic patients. Biol Psychiatry40:930-932.
14.
Chafee MV, Goldman-Rakic PS. 1998. Matching patterns of activity in primate prefrontal area 8a and parietal area 7ip neurons during a spatial working memory task. J Neurophysiol79:2919-2940.
15.
Cohen JD, Braver TS, Brown JW. 2002Computational perspectives on dopamine function in prefrontal cortex. Curr Opinion in Neurobiol12:223-229.
16.
Compte A, Brunel N, Goldman-Rakic PS, Wang XJ. 2000. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Cereb Cortex10:910-923.
17.
Compte A, Constantinidis C, Tegner J, Raghavachari S, Chafee MV, Goldman-Rakic PS, and others. 2003. Temporally irregular mnemonic persistent activity in prefrontal neurons of monkeys during a delayed response task. J Neurophysiol28:28.
18.
Constantinidis C, Franowicz MN, Goldman-Rakic PS. 2001a. Coding specificity in cortical microcircuits: a multiple electrode analysis of primate prefrontal cortex. J Neurosci21:3646-3655.
19.
Constantinidis C, Franowicz MN, Goldman-Rakic PS. 2001b. The sensory nature of mnemonic representation in the primate prefrontal cortex. Nat Neurosci4:311-316.
20.
Constantinidis C, Goldman-Rakic PS. 2002. Correlated discharges among putative pyramidal neurons and interneurons in the primate prefrontal cortex. J Neurophysiol88:3487-3497.
21.
Constantinidis C, Steinmetz MA. 1996. Neuronal activity in posterior parietal area 7a during the delay periods of a spatial memory task. J Neurophysiol76:1352-1355.
22.
Constantinidis C, Steinmetz MA. 2001. Neuronal responses in area 7a to multiple stimulus displays: II. Responses are suppressed at the cued location. Cereb Cortex11:592-597.
23.
Constantinidis C, Williams GV, Goldman-Rakic PS. 2002. A role for inhibition in shaping the temporal flow of information in prefrontal cortex. Nat Neurosci5:175-180.
24.
Cornette L, Dupont P, Orban GA. 2002. The neural substrate of orientation short-term memory and resistance to distractor items. Eur J Neurosci15:165-175.
25.
Courtney SM, Ungerleider LG, Keil K, Haxby JV. 1997. Transient and sustained activity in a distributed neural system for human working memory. Nature386:608-611.
26.
Curtis CE, D’Esposito M.2003. Persistent activity in the prefrontal cortex during working memory. Trends Cogn Sci7:415-423.
27.
di Pellegrino G, Wise SP. 1993a. Effects of attention on visuomotor activity in the premotor and prefrontal cortex of a primate. Somatosens Mot Res10:245-262.
28.
di Pellegrino G, Wise SP. 1993b. Visuospatial versus visuomotor activity in the premotor and prefrontal cortex of a primate. J Neurosci13:1227-1243.
29.
DiCarlo JJ, Maunsell JH. 2003. Anterior inferotemporal neurons of monkeys engaged in object recognition can be highly sensitive to object retinal position. J Neurophysiol89:3264-3278.
30.
Durstewitz D, Seamans JK, Sejnowski TJ. 2000. Dopamine-mediated stabilization of delay-period activity in a network model of pre-frontal cortex. J Neurophysiol83:1733-1750.
31.
Egorov AV, Hamam BN, Fransen E, Hasselmo ME, Alonso AA. 2002. Graded persistent activity in entorhinal cortex neurons. Nature420:173-178.
32.
Ettinger U, Kumari V, Crawford TJ, Corr PJ, Das M, Zachariah E, and others. 2004. Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia. J Psychiatr Res38:177-184.
33.
Everling S, Tinsley CJ, Gaffan D, Duncan J.2002. Filtering of neural signals by focused attention in the monkey prefrontal cortex. Nat Neurosci5:671-676.
34.
Fuller R, Nopoulos P, Arndt S, O’Leary D, Ho BC, Andreasen NC. 2002. Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry159:1183-1189.
35.
Funahashi S, Bruce CJ, Goldman-Rakic PS. 1989. Mnemonic coding of visual space in the monkey’s dorsolateral prefrontal cortex. J Neurophysiol61:331-349.
36.
Funahashi S, Bruce CJ, Goldman-Rakic PS. 1993. Dorsolateral pre-frontal lesions and oculomotor delayed-response performance: evidence for mnemonic “scotomas.”J Neurosci13:1479-1497.
37.
Funahashi S, Chafee MV, Goldman-Rakic PS. 1993. Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task. Nature365:753-756.
38.
Fuster JM, Alexander GE. 1971. Neuron activity related to short-term memory. Science173:652-654.
39.
Fuster JM, Alexander GE. 1973. Firing changes in cells of the nucleus medialis dorsalis associated with delayed response behavior. Brain Res61:79-91.
40.
Gao WJ, Krimer LS, Goldman-Rakic PS. 2001. Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proc Natl Acad Sci U S A98:295-300.
41.
Gao WJ, Wang Y, Goldman-Rakic PS. 2003. Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex. J Neurosci23:1622-1630.
42.
Gasperoni TL, Ekelund J, Huttunen M, Palmer CG, Tuulio-Henriksson A, Lonnqvist J, and others. 2003. Genetic linkage and association between chromosome 1q and working memory function in schizophrenia. Am J Med Genet116B:8-16.
43.
Glimcher PW, Sparks DL. 1992. Movement selection in advance of action in the superior colliculus. Nature355:542-545.
44.
Gnadt JW, Andersen RA. 1988. Memory related motor planning activity in posterior parietal cortex of macaque. Exp Brain Res70:216-220.
45.
Goldman-Rakic PS. 1987. Circuitry of the prefrontal cortex and the regulation of behavior by representational knowledge. In: Plum F, Mountcastle VB, editors. Handbook of physiology. Bethesda (MD): American Physiological Society. p 373-417.
46.
Goldman-Rakic PS. 1994. Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci6:348-357.
47.
Grunewald A, Linden JF, Andersen RA. 1999. Responses to auditory stimuli in macaque lateral intraparietal area: I. Effects of training. J Neurophysiol82:330-342.
48.
Gutkin BS, Laing CR, Colby CL, Chow CC, Ermentrout GB. 2001. Turning on and off with excitation: the role of spike-timing asynchrony and synchrony in sustained neural activity. J Comput Neurosci11:121-134.
49.
Henze DA, Gonzalez-Burgos GR, Urban NN, Lewis DA, Barrionuevo G.2000. Dopamine increases excitability of pyramidal neurons in primate prefrontal cortex. J Neurophysiol84:2799-2809.
50.
Hikosaka O, Sakamoto M, Usui S.1989. Functional properties of monkey caudate neurons: I. Activities related to saccadic eye movements. J Neurophysiol61:780-798.
51.
Hikosaka O, Wurtz RH. 1983. Visual and oculomotor functions of monkey substantia nigra pars reticulata: III. Memory-contingent visual and saccade responses. J Neurophysiol49:1268-1284.
52.
Jacobsen CF. 1936. Studies of cerebral function in primates. Comp Psychol Monogr13:1-68.
53.
Jonides J, Smith EE, Koeppe RA, Awh E, Minoshima S, Mintun MA. 1993. Spatial working memory in humans as revealed by PET. Nature363:623-625.
54.
Kimura M, Aosaki T, Hu Y, Ishida A, Watanabe K.1992. Activity of primate putamen neurons is selective to the mode of voluntary movement: visually guided, self-initiated or memory-guided. Exp Brain Res89:473-477.
55.
Kritzer MF, Goldman-Rakic PS. 1995. Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the rhesus monkey. J Comp Neurol359:131-143.
56.
Kubota K, Niki H.1971. Prefrontal cortical unit activity and delayed alternation performance in monkeys. J Neurophysiol34:337-347.
57.
Leon MI, Shadlen MN. 1999. Effect of expected reward magnitude on the response of neurons in the dorsolateral prefrontal cortex of the macaque. Neuron24:415-425.
58.
Levitt JB, Lewis DA, Yoshioka T, Lund JS. 1993. Topography of pyramidal neuron intrinsic connections in macaque monkey pre-frontal cortex (areas 9 and 46). J Comp Neurol338:360-376.
59.
Lewis DA, Volk DW, Hashimoto T.2003. Selective alterations in pre-frontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology (Berl)9:9.
60.
Lisman JE, Fellous JM, Wang XJ. 1998. A role for NMDA-receptor channels in working memory. Nat Neurosci1:273-275.
61.
Marshuetz C, Smith EE, Jonides J, DeGutis J, Chenevert TL. 2000. Order information in working memory: fMRI evidence for parietal and prefrontal mechanisms. J Cogn Neurosci12:130-144.
62.
Mazzoni P, Bracewell RM, Barash S, Andersen RA. 1996. Spatially tuned auditory responses in area LIP of macaques performing delayed memory saccades to acoustic targets. J Neurophysiol75:1233-1241.
63.
McGorry PD. 2003. Spatial working memory ability is a marker of risk-for-psychosis. Psychol Med33:1239-1247.
64.
Milner B.1963. Effects of different brain lesions on card sorting. Arch Neurol9:100-110.
65.
Munk MH, Linden DE, Muckli L, Lanfermann H, Zanella FE, Singer W, and others. 2002. Distributed cortical systems in visual short-term memory revealed by event-related functional magnetic resonance imaging. Cereb Cortex12:866-876.
66.
Murphy FC, Michael A, Robbins TW, Sahakian BJ. 2003. Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance. Psychol Med33:455-467.
67.
Nakamura K, Colby CL. 2000. Visual, saccade-related, and cognitive activation of single neurons in monkey extrastriate area V3A. J Neurophysiol84:677-692.
68.
Niendam TA, Bearden CE, Rosso IM, Sanchez LE, Hadley T, Nuechterlein KH, and others. 2003. A prospective study of childhood neurocognitive functioning in schizophrenic patients and their siblings. Am J Psychiatry160:2060-2062.
69.
Niki H, Watanabe M.1976. Prefrontal unit activity and delayed response: relation to cue location versus direction of response. Brain Res105:79-88.
70.
Owen AM, Stern CE, Look RB, Tracey I, Rosen BR, Petrides M.1998. Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex. Proc Natl Acad Sci U S A95:7721-7726.
71.
Pantelis C, Barnes TR, Nelson HE, Tanner S, Weatherley L, Owen AM, and others. 1997. Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain120:1823-1843.
72.
Park S, Holzman PS. 1992. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry49:975-982.
73.
Park S, Holzman PS, Goldman-Rakic PS. 1995. Spatial working memory deficits in the relatives of schizophrenic patients. Arch Gen Psychiatry52:821-828.
74.
Park S, Puschel J, Sauter BH, Rentsch M, Hell D.1999. Spatial working memory deficits and clinical symptoms in schizophrenia: a 4-month follow-up study. Biol Psychiatry46:392-400.
75.
Pesaran B, Pezaris JS, Sahani M, Mitra PP, Andersen RA. 2002. Temporal structure in neuronal activity during working memory in macaque parietal cortex. Nat Neurosci5:805-811.
76.
Platt ML, Glimcher PW. 1999. Neural correlates of decision variables in parietal cortex. Nature400:233-238.
77.
Powell KD, Goldberg ME. 2000. Response of neurons in the lateral intraparietal area to a distractor flashed during the delay period of a memory-guided saccade. J Neurophysiol84:301-310.
78.
Pucak ML, Levitt JB, Lund JS, Lewis DA. 1996. Patterns of intrinsic and associational circuitry in monkey prefrontal cortex. J Comp Neurol376:614-630.
79.
Purcell R, Maruff P, Kyrios M, Pantelis C.1998. Neuropsychological deficits in obsessive-compulsive disorder: a comparison with unipolar depression, panic disorder, and normal controls. Arch Gen Psychiatry55:415-423.
80.
Quintana J, Fuster JM. 1992. Mnemonic and predictive functions of cortical neurons in a memory task. Neuroreport3:721-724.
81.
Rainer G, Asaad WF, Miller EK. 1998a. Memory fields of neurons in the primate prefrontal cortex. Proc Natl Acad Sci U S A95:15008-15013.
82.
Rainer G, Asaad WF, Miller EK. 1998b. Selective representation of relevant information by neurons in the primate prefrontal cortex. Nature393:577-579.
83.
Rao SC, Rainer G, Miller EK. 1997. Integration of what and where in the primate prefrontal cortex. Science276:821-824.
84.
Rao SG, Williams GV, Goldman-Rakic PS. 1999. Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. J Neurophysiol81:1903-1916.
85.
Rao SG, Williams GV, Goldman-Rakic PS. 2000. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of pre-frontal cortical neurons engaged by working memory. J Neurosci20:485-494.
86.
Renart A, Brunel N, Wang X-J.2003. Mean-field theory of recurrent cortical networks: working memory circuits with irregularly spiking neurons. In: Feng J, editor. Computational neuroscience: a comprehensive approach. Boca Raton (FL): CRC Press. p 432-490.
87.
Renart A, Song P, Wang X-J.2003. Robust spatial working memory in a heterogeneous network model with homeostatic synaptic scaling. Neuron38:473-485.
88.
Reuter B, Kathmann N, Ettinger U, Kumari V, Crawford TJ, Corr PJ, and others. 2004. Using saccade tasks as a tool to analyze executive dysfunctions in schizophrenia. Acta Psychol (Amst)115:255-269.
89.
Robinson DL, Petersen SE, Keys W.1986. Saccade-related and visual activities in the pulvinar nuclei of the behaving rhesus monkey. Exp Brain Res62:625-634.
90.
Rolls ET. 1999. Spatial view cells and the representation of place in the primate hippocampus. Hippocampus9:467-480.
91.
Romanski LM, Tian B, Fritz J, Mishkin M, Goldman-Rakic PS, Rauschecker JP. 1999. Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex. Nat Neurosci2:1131-1136.
92.
Rowe JB, Passingham RE. 2001. Working memory for location and time: activity in prefrontal area 46 relates to selection rather than maintenance in memory. Neuroimage14:77-86.
93.
Russo GS, Bruce CJ. 1996. Neurons in the supplementary eye field of rhesus monkeys code visual targets and saccadic eye movements in an oculocentric coordinate system. J Neurophysiol76:825-848.
94.
Sakai K, Rowe JB, Passingham RE. 2002. Active maintenance in pre-frontal area 46 creates distractorresistant memory. Nat Neurosci5:479-484.
95.
Sawaguchi T, Goldman-Rakic PS. 1991. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science251:947-950.
96.
Sawaguchi T, Goldman-Rakic PS. 1994. The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol71:515-528.
97.
Sawaguchi T, Yamane I.1999. Properties of delay-period neuronal activity in the monkey dorsolateral prefrontal cortex during a spatial delayed matching-to-sample task. J Neurophysiol82:2070-2080.
98.
Seamans JK, Yang CR. 2004. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 74:1-58.
Seung HS, Lee DD, Reis BY, Tank DW. 2000. Stability of the memory of eye position in a recurrent network of conductance-based model neurons. Neuron26:259-271.
101.
Shafi M, Bodner M, Zhou Y, Fuster JM. 2003. Measurements of neuronal variability during working memory: implications for theoretical and computational models. Soc Neursci Abstr33:518.17.
102.
Sharp PE, Blair HT, Cho J.2001. The anatomical and computational basis of the rat head-direction cell signal. Trends Neurosci24:289-294.
103.
Sommer MA, Wurtz RH. 2004. What the brainstem tells the frontal cortex I. Oculomotor signals sent from superior colliculus to frontal eye field via mediodorsal thalamus. J Neurophysiol91:1381-1402.
104.
Stern CE, Sherman SJ, Kirchhoff BA, Hasselmo ME. 2001. Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli. Hippocampus11:337-346.
105.
Sullivan EV, Mathalon DH, Zipursky RB, Kersteen-Tucker Z, Knight RT, Pfefferbaum A.1993. Factors of the Wisconsin Card Sorting Test as measures of frontal-lobe function in schizophrenia and in chronic alcoholism. Psychiatry Res46:175-199.
106.
Super H, Spekreijse H, Lamme VA. 2001. A neural correlate of working memory in the monkey primary visual cortex. Science293:120-124.
107.
Suzuki WA, Miller EK, Desimone R.1997. Object and place memory in the macaque entorhinal cortex. J Neurophysiol78:1062-1081.
108.
Takeda K, Funahashi S.2002. Prefrontal task-related activity representing visual cue location or saccade direction in spatial working memory tasks. J Neurophysiol87:567-588.
109.
Tegner J, Compte A, Wang XJ. 2002. The dynamical stability of reverberatory neural circuits. Biol Cybern87:471-481.
110.
Ungerleider LG, Courtney SM, Haxby JV. 1998. A neural system for human visual working memory. Proc Natl Acad Sci U S A95:883-890.
111.
Vaadia E, Benson DA, Hienz RD, Goldstein MH Jr.1986. Unit study of monkey frontal cortex: active localization of auditory and of visual stimuli. J Neurophysiol56:934-952.
112.
Wallis JD, Anderson KC, Miller EK. 2001. Single neurons in pre-frontal cortex encode abstract rules. Nature411:953-956.
113.
Wang M, Vijayraghavan S, Goldman-Rakic PS. 2004. Selective D2 receptor actions on the functional circuitry of working memory. Science303:853-856.
114.
Wang XJ. 1999. Synaptic basis of cortical persistent activity: the importance of NMDA receptors to working memory. J Neurosci19:9587-9603.
Wang XJ, Tegner J, Constantinidis C, Goldman-Rakic PS. 2004. Division of labor among distinct inhibitory neurons in a cortical microcircuit of working memory. Proc Natl Acad Sci U S A101:1368-1373.
117.
White IM, Wise SP. 1999. Rule-dependent neuronal activity in the pre-frontal cortex. Exp Brain Res126:315-335.
118.
Williams GV, Goldman-Rakic PS. 1995. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature376:572-575.
119.
Wilson FA, O’Scalaidhe SP, Goldman-Rakic PS. 1993. Dissociation of object and spatial processing domains in primate prefrontal cortex. Science260:1955-1958.
120.
Wilson FA, O’Scalaidhe SP, Goldman-Rakic PS. 1994. Functional synergism between putative gamma-aminobutyrate-containing neurons and pyramidal neurons in prefrontal cortex. Proc Natl Acad Sci U S A91:4009-4013.
121.
Wood SJ, Pantelis C, Proffitt T, Phillips LJ, Stuart GW, Buchanan JA, and others. 2003. Spatial working memory ability is a marker of risk-for-psychosis. Psychol Med33:1239-1247.
