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Graded persistent activity in entorhinal cortex neurons


Working memory represents the ability of the brain to hold externally or internally driven information for relatively short periods of time1,2. Persistent neuronal activity is the elementary process underlying working memory but its cellular basis remains unknown. The most widely accepted hypothesis is that persistent activity is based on synaptic reverberations in recurrent circuits. The entorhinal cortex in the parahippocampal region is crucially involved in the acquisition, consolidation and retrieval of long-term memory traces for which working memory operations are essential2. Here we show that individual neurons from layer V of the entorhinal cortex—which link the hippocampus to extensive cortical regions3—respond to consecutive stimuli with graded changes in firing frequency that remain stable after each stimulus presentation. In addition, the sustained levels of firing frequency can be either increased or decreased in an input-specific manner. This firing behaviour displays robustness to distractors; it is linked to cholinergic muscarinic receptor activation, and relies on activity-dependent changes of a Ca2+-sensitive cationic current. Such an intrinsic neuronal ability to generate graded persistent activity constitutes an elementary mechanism for working memory.

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  1. 1

    Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995)

  2. 2

    Fuster, J. M. Network memory. Trends Neurosci. 20, 451–459 (1997)

  3. 3

    Insausti, R., Herrero, M. T. & Witter, M. P. Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus 7, 146–183 (1997)

  4. 4

    Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiat. 20, 11–21 (1957)

  5. 5

    Squire, L. R. & Zola-Morgan, S. The medial temporal lobe memory system. Science 253, 1380–1386 (1991)

  6. 6

    Young, B., Otto, T., Fox, G. D. & Eichenbaum, H. Memory representation within the parahippocampal region. J. Neurosci. 17, 5183–5195 (1997)

  7. 7

    Suzuki, W. A., Miller, E. K. & Desimone, R. Object and place memory in the macaque entorhinal cortex. J. Neurophysiol. 78, 1062–1081 (1997)

  8. 8

    Bunsey, M. & Eichenbaum, H. Critical role of the parahippocampal region for paired-associate learning in rats. Behav. Neurosci. 107, 740–747 (1993)

  9. 9

    Higuchi, S. & Miyashita, Y. Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions. Proc. Natl Acad. Sci. USA 93, 739–743 (1996)

  10. 10

    Stern, C. E., Sherman, S. J., Kirchhoff, B. A. & Hasselmo, M. E. Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli. Hippocampus 11, 337–346 (2001)

  11. 11

    Room, P. & Groenewegen, H. J. Connections of the parahippocampal cortex. I. Cortical afferents. J. Comp. Neurol. 251, 415–450 (1986)

  12. 12

    Rempel-Clower, N. L. & Barbas, H. The laminar pattern of connections between prefrontal and anterior temporal cortices in the Rhesus monkey is related to cortical structure and function. Cereb. Cortex 10, 851–865 (2000)

  13. 13

    Naber, P. A., Lopes da Silva, F. H. & Witter, M. P. Reciprocal connections between the entorhinal cortex and hippocampal fields CA1 and the subiculum are in register with the projections from CA1 to the subiculum. Hippocampus 11, 99–104 (2001)

  14. 14

    Alonso, J. R. & Amaral, D. G. Cholinergic innervation of the primate hippocampal formation. I. Distribution of choline acetyltransferase immunoreactivity in the Macaca fascicularis and Macaca mulatta monkeys. J. Comp. Neurol. 355, 135–170 (1995)

  15. 15

    Hasselmo, M. E. Neuromodulation: acetylcholine and memory consolidation. Trends Cogn. Sci 3, 351–359 (1999)

  16. 16

    Krnjevic, K. Central cholinergic mechanisms and function. Prog. Brain Res. 1993, 285–292 (1993)

  17. 17

    Hamam, B. N., Kennedy, T. E., Alonso, A. & Amaral, D. G. Morphological and electrophysiological characteristics of layer V neurons of the rat medial entorhinal cortex. J. Comp. Neurol. 418, 457–472 (2000)

  18. 18

    Andrade, R. Cell excitation enhances muscarinic cholinergic responses in rat association cortex. Brain Res. 548, 81–93 (1991)

  19. 19

    Fraser, D. D. & MacVicar, B. A. Cholinergic-dependent plateau potential in hippocampal CA1 pyramidal neurons. J. Neurosci. 16, 4113–4128 (1996)

  20. 20

    Haj-Dahmane, S. & Andrade, R. Ionic mechanism of the slow afterdepolarization induced by muscarinic receptor activation in rat prefrontal cortex. J. Neurophysiol. 80, 1197–1210 (1998)

  21. 21

    Klink, R. & Alonso, A. Muscarinic modulation of the oscillatory and repetitive firing properties of entorhinal cortex layer II neurons. J. Neurophysiol. 77, 1813–1828 (1997)

  22. 22

    Fransén, E., Alonso, A. A. & Hasselmo, M. E. Simulations of the role of the muscarinic-activated calcium-sensitive nonspecific cation current INCM in entorhinal neuronal activity during delayed matching tasks. J. Neurosci. 22, 1081–1097 (2002)

  23. 23

    Boeijinga, P. H. & Lopes da Silva, F. H. Modulations of EEG activity in the entorhinal cortex and forebrain olfactory areas during odour sampling. Brain Res. 478, 257–268 (1989)

  24. 24

    Wang, X.-J. Synaptic reverberation underlying mnemonic persistent activity. Trends Neurosci. 24, 427–488 (2001)

  25. 25

    Partridge, L. D. & Valenzuela, C. F. Block of hippocampal CAN channels by flufenamate. Brain Res. 867, 143–148 (2000)

  26. 26

    Lisman, J. E., Fellous, J. M. & Wang, X. J. A role for NMDA-receptor channels in working memory. Nature Neurosci. 1, 273–275 (1998)

  27. 27

    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 26, 259–271 (2000)

  28. 28

    Insausti, R., Amaral, D. G. & Cowan, W. M. The entorhinal cortex of the monkey: II. Cortical afferents. J. Comp. Neurol. 264, 356–395 (1987)

  29. 29

    Marder, E., Abbott, L. F., Turrigiano, G. G., Liu, Z. & Golowasch, J. Memory from the dynamics of intrinsic membrane currents. Proc. Natl Acad. Sci. USA 93, 13481–13486 (1996)

  30. 30

    Dickson, C. T. & Alonso, A. Muscarinic induction of synchronous population activity in the entorhinal cortex. J. Neurosci. 17, 6729–6744 (1997)

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We thank G. Buzsáki, M. Petrides and W. A. Suzuki for comments on the manuscript. This work was supported by the Canadian Institutes of Health Research and the U.S. National Institutes of Mental Health.

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Correspondence to Angel A. Alonso.

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The authors declare that they have no competing financial interests.

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Figure 1: Muscarinic-dependent persistent activity.
Figure 2: Graded persistent activity.
Figure 3: Synaptic induction of persistent activity.
Figure 4: Persistent activity requires activity-dependent Ca2+ influx and a non-specific cation current.


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