Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Heterogeneity in the pyramidal network of the medial prefrontal cortex

Abstract

The prefrontal cortex is specially adapted to generate persistent activity that outlasts stimuli and is resistant to distractors, presumed to be the basis of working memory. The pyramidal network that supports this activity is unknown. Multineuron patch-clamp recordings in the ferret medial prefrontal cortex showed a heterogeneity of synapses interconnecting distinct subnetworks of different pyramidal cells. One subnetwork was similar to the pyramidal network commonly found in primary sensory areas, consisting of accommodating pyramidal cells interconnected with depressing synapses. The other subnetwork contained complex pyramidal cells with dual apical dendrites displaying nonaccommodating discharge patterns; these cells were hyper-reciprocally connected with facilitating synapses displaying pronounced synaptic augmentation and post-tetanic potentiation. These cellular, synaptic and network properties could amplify recurrent interactions between pyramidal neurons and support persistent activity in the prefrontal cortex.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Facilitating connections in the mPFC.
Figure 2: Recorded and modeled synaptic connections in the mPFC and visual cortex.
Figure 3: Distribution of model parameters (DFUA) of all connections studied in the mPFC and visual cortex.
Figure 4: Excitatory synaptic subtypes in the mPFC.
Figure 5: Synaptic augmentation and post-tetanic potentiation (PTP) in different types of excitatory connections in the mPFC.
Figure 6: Functional and structural architecture of the layer 5 pyramidal network in the mPFC.

References

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

    CAS  Article  Google Scholar 

  2. Miller, E.K., Erickson, C.A. & Desimone, R. Neural mechanisms of visual working memory in prefrontal cortex of the macaque. J. Neurosci. 16, 5154–5167 (1996).

    CAS  Article  Google Scholar 

  3. Goldman-Rakic, P.S. Architecture of the prefrontal cortex and the central executive. Ann. NY Acad. Sci. 769, 71–83 (1995).

    CAS  Article  Google Scholar 

  4. Wang, X.J. Synaptic reverberation underlying mnemonic persistent activity. Trends Neurosci. 24, 455–463 (2001).

    CAS  Article  Google Scholar 

  5. Durstewitz, D., Seamans, J.K. & Sejnowski, T.J. Neurocomputational models of working memory. Nat. Neurosci. 3, 1184–1191 (2000).

    CAS  Article  Google Scholar 

  6. Hempel, C.M., Hartman, K.H., Wang, X.J., Turrigiano, G.G. & Nelson, S.B. Multiple forms of short-term plasticity at excitatory synapses in rat medial prefrontal cortex. J. Neurophysiol. 83, 3031–3041 (2000).

    CAS  Article  Google Scholar 

  7. Thomson, A.M., Deuchars, J. & West, D.C. Single axon excitatory postsynaptic potentials in neocortical interneurons exhibit pronounced paired pulse facilitation. Neuroscience 54, 347–360 (1993).

    CAS  Article  Google Scholar 

  8. Markram, H., Wang, Y. & Tsodyks, M. Differential signaling via the same axon of neocortical pyramidal neurons. Proc. Natl. Acad. Sci. USA 95, 5323–5328 (1998).

    CAS  Article  Google Scholar 

  9. Tsodyks, M.V. & Markram, H. The neural code between neocortical pyramidal neurons depends on neurotransmitter release probability. Proc. Natl. Acad. Sci. USA 94, 719–723 (1997).

    CAS  Article  Google Scholar 

  10. Thomson, A.M. Facilitation, augmentation and potentiation at central synapses. Trends Neurosci. 23, 305–312 (2000).

    CAS  Article  Google Scholar 

  11. Reyes, A. et al. Target-cell–specific facilitation and depression in neocortical circuits. Nat. Neurosci. 1, 279–285 (1998).

    CAS  Article  Google Scholar 

  12. Reyes, A. & Sakmann, B. Developmental switch in the short-term modification of unitary EPSPs evoked in layer 2/3 and layer 5 pyramidal neurons of rat neocortex. J. Neurosci. 19, 3827–3835 (1999).

    CAS  Article  Google Scholar 

  13. Abbott, L.F., Varela, J.A., Sen, K. & Nelson, S.B. Synaptic depression and cortical gain control. Science 275, 220–224 (1997).

    CAS  Article  Google Scholar 

  14. Mercer, A. et al. Excitatory connections made by presynaptic cortico-cortical pyramidal cells in layer 6 of the neocortex. Cereb. Cortex 15, 1485–1496 (2005).

    Article  Google Scholar 

  15. Thomson, A.M., Deuchars, J. & West, D.C. Large, deep layer pyramid-pyramid single axon EPSPs in slices of rat motor cortex display paired pulse and frequency-dependent depression, mediated presynaptically and self-facilitation, mediated postsynaptically. J. Neurophysiol. 70, 2354–2369 (1993).

    CAS  Article  Google Scholar 

  16. Thomson, A.M. Activity-dependent properties of synaptic transmission at two classes of connections made by rat neocortical pyramidal axons in vitro. J. Physiol. (Lond.) 502, 131–147 (1997).

    CAS  Article  Google Scholar 

  17. Thomson, A.M., West, D.C., Wang, Y. & Bannister, A.P. Synaptic connections and small circuits involving excitatory and inhibitory neurons in layers 2–5 of adult rat and cat neocortex: triple intracellular recordings and biocytin labelling in vitro. Cereb. Cortex 12, 936–953 (2002).

    Article  Google Scholar 

  18. Varela, J.A. et al. A quantitative description of short-term plasticity at excitatory synapses in layer 2/3 of rat primary visual cortex. J. Neurosci. 17, 7926–7940 (1997).

    CAS  Article  Google Scholar 

  19. Markram, H., Lubke, J., Frotscher, M., Roth, A. & Sakmann, B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. J. Physiol. (Lond.) 500, 409–440 (1997).

    CAS  Article  Google Scholar 

  20. Galarreta, M. & Hestrin, S. Frequency-dependent synaptic depression and the balance of excitation and inhibition in the neocortex. Nat. Neurosci. 1, 587–594 (1998).

    CAS  Article  Google Scholar 

  21. Tarczy-Hornoch, K., Martin, K.A., Stratford, K.J. & Jack, J.J. Intracortical excitation of spiny neurons in layer 4 of cat striate cortex in vitro. Cereb. Cortex 9, 833–843 (1999).

    CAS  Article  Google Scholar 

  22. West, D.C., Mercer, A., Kirchhecker, S., Morris, O.T. & Thomson, A.M. Layer 6 cortico-thalamic pyramidal cells preferentially innervate interneurons and generate facilitating EPSPs. Cereb. Cortex 16, 200–211.

  23. Gupta, A., Wang, Y. & Markram, H. Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287, 273–278 (2000).

    CAS  Article  Google Scholar 

  24. Zucker, R.S. & Regehr, W.G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).

    CAS  Article  Google Scholar 

  25. Mason, A., Nicoll, A. & Stratford, K. Synaptic transmission between individual pyramidal neurons of the rat visual cortex in vitro. J. Neurosci. 11, 72–84 (1991).

    CAS  Article  Google Scholar 

  26. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807 (2004).

    CAS  Article  Google Scholar 

  27. Elston, G.N. Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function. Cereb. Cortex 13, 1124–1138 (2003).

    Article  Google Scholar 

  28. Markram, H. A network of tufted layer 5 pyramidal neurons. Cereb. Cortex 7, 523–533 (1997).

    CAS  Article  Google Scholar 

  29. Giguere, M. & Goldman-Rakic, P.S. Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J. Comp. Neurol. 277, 195–213 (1988).

    CAS  Article  Google Scholar 

  30. Cavada, C. & Goldman-Rakic, P.S. Posterior parietal cortex in rhesus monkey: II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe. J. Comp. Neurol. 287, 422–445 (1989).

    CAS  Article  Google Scholar 

  31. Gabbott, P.L., Warner, T.A., Jays, P.R., Salway, P. & Busby, S.J. Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J. Comp. Neurol. 492, 145–177 (2005).

    Article  Google Scholar 

  32. Yuste, R., Gutnick, M.J., Saar, D., Delaney, K.R. & Tank, D.W. Ca2+ accumulations in dendrites of neocortical pyramidal neurons: an apical band and evidence for two functional compartments. Neuron 13, 23–43 (1994).

    CAS  Article  Google Scholar 

  33. Larkum, M.E., Zhu, J.J. & Sakmann, B. A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature 398, 338–341 (1999).

    CAS  Article  Google Scholar 

  34. Rhodes, P.A. & Llinas, R.R. Apical tuft input efficacy in layer 5 pyramidal cells from rat visual cortex. J. Physiol. (Lond.) 536, 167–187 (2001).

    CAS  Article  Google Scholar 

  35. Berger, T., Larkum, M.E. & Luscher, H.R. High I(h) channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. J. Neurophysiol. 85, 855–868 (2001).

    CAS  Article  Google Scholar 

  36. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci. 18, 7613–7624 (1998).

    CAS  Article  Google Scholar 

  37. Kalisman, N., Silberberg, G. & Markram, H. The neocortical microcircuit as a tabula rasa. Proc. Natl. Acad. Sci. USA 102, 880–885 (2005).

    CAS  Article  Google Scholar 

  38. Douglas, R.J., Mahowald, M., Martin, K.A. & Stratford, K.J. The role of synapses in cortical computation. J. Neurocytol. 25, 893–911 (1996).

    CAS  Article  Google Scholar 

  39. Mongillo, G., Amit, D.J. & Brunel, N. Retrospective and prospective persistent activity induced by Hebbian learning in a recurrent cortical network. Eur. J. Neurosci. 18, 2011–2024 (2003).

    Article  Google Scholar 

  40. McCormick, D.A. Brain calculus: neural integration and persistent activity. Nat. Neurosci. 4, 113–114 (2001).

    CAS  Article  Google Scholar 

  41. Gao, W.J., Krimer, L.S. & Goldman-Rakic, P.S. Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proc. Natl. Acad. Sci. USA 98, 295–300 (2001).

    CAS  Article  Google Scholar 

  42. Fisher, S.A., Fischer, T.M. & Carew, T.J. Multiple overlapping processes underlying short-term synaptic enhancement. Trends Neurosci. 20, 170–177 (1997).

    CAS  Article  Google Scholar 

  43. Magleby, K.L. Short-term changes in synaptic efficacy. Synaptic Function (eds. Edelman, G.M., Gall, W.E. & Cowan, W.M.) 21–56 (Wiley, New York, 1987).

    Google Scholar 

  44. Larkum, M.E., Kaiser, K.M. & Sakmann, B. Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a critical frequency of back-propagating action potentials. Proc. Natl. Acad. Sci. USA 96, 14600–14604 (1999).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This paper is dedicated to Patricia S. Goldman-Rakic, who wholeheartedly supported and supervised this study before she passed away suddenly on July 31 2003. She will always be an inspiration for our work. We are grateful to D.A. McCormick, T. Koos and W.J. Gao for comments on the experimental design; O. Melamed for testing mathematical synaptic modeling; and M. Pappy and A. Begovic for technical assistance. We also thank M. Tsodyks for performing preliminary network modeling studies to better understand the potential functions of facilitation and PTP in recurrent excitation and for his comments on the paper. This work was supported by the National Institute of Mental Health (grant RO1), the Natalie V. Zucker Award, the Charlton Research grants to Tufts University School of Medicine and, in part, by the National Alliance for Autism Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yun Wang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Facilitating time constant (F) vs. ages of the ferrets. (PDF 56 kb)

Supplementary Fig. 2

Synaptic facilitation between layer 5 pyramidal neurons in different cortical areas of juvenile rats (p13 – p17). (PDF 57 kb)

Supplementary Fig. 3

The EPSP amplitudes and patterns of three E–types of excitatory connections during the train stimulations. (PDF 46 kb)

Supplementary Table 1

Structural and functional architecture of the layer 5 pyramidal networks in ferret mPFC and VC. (PDF 104 kb)

Supplementary Table 2

E-Types vs. multiple parameters of PCs and synaptic connections. (PDF 57 kb)

Supplementary Table 3

Quantitative comparison of complex and simple PCs in the ferret mPFC. (PDF 74 kb)

Supplementary Table 4 (PDF 45 kb)

Supplementary Methods (PDF 322 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, Y., Markram, H., Goodman, P. et al. Heterogeneity in the pyramidal network of the medial prefrontal cortex. Nat Neurosci 9, 534–542 (2006). https://doi.org/10.1038/nn1670

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1670

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing