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Nicotinic control of axon excitability regulates thalamocortical transmission

Abstract

The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability. Exogenous nicotine enhanced the probability and synchrony of evoked action potential discharges along thalamocortical axons in vitro, but had little effect on synaptic release mechanisms. In vivo, the blockade of nAChRs in the thalamocortical pathway reduced sound-evoked cortical responses, especially those evoked by sounds near the acoustic threshold. These data indicate that endogenous acetylcholine activates nAChRs in the thalamocortical pathway to lower the threshold for thalamocortical transmission and to increase the magnitude of sensory-evoked cortical responses. Our results show that a neurotransmitter can modulate sensory processing by regulating conduction along myelinated thalamocortical axons.

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Figure 1: Postsynaptic and axon spike responses to stimulation of adult thalamocortical axons.
Figure 2: Nicotine enhances success rate for thalamocortical EPSCs.
Figure 3: Nicotine enhances success rate for axon spikes in subcortical white matter.
Figure 4: Minimal EPSCs in thalamocortical slices with MGv severed.
Figure 5: Nicotine decreases the latency and latency variability of axon spikes.
Figure 6: Blockade of nAChRs in thalamic white matter in vivo delays onset latency and decreases amplitude of tone-evoked responses in auditory cortex.

References

  1. Castro-Alamancos, M.A. & Connors, B.W. Thalamocortical synapses. Prog. Neurobiol. 51, 581–606 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Volgushev, M., Voronin, L.L., Chistiakova, M., Artola, A. & Singer, W. All-or-none excitatory postsynaptic potentials in the rat visual cortex. Eur. J. Neurosci. 7, 1751–1760 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Stratford, K.J., Tarczy-Hornoch, K., Martin, K.A., Bannister, N.J. & Jack, J.J. Excitatory synaptic inputs to spiny stellate cells in cat visual cortex. Nature 382, 258–261 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Gil, Z., Connors, B.W. & Amitai, Y. Efficacy of thalamocortical and intracortical synaptic connections: quanta, innervation and reliability. Neuron 23, 385–397 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. McCormick, D.A. Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamic activity. Prog. Neurobiol. 39, 337–388 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Steriade, M. Acetylcholine systems and rhythmic activities during the waking-sleep cycle. Prog. Brain Res. 145, 179–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Edeline, J.M. The thalamo-cortical auditory receptive fields: regulation by the states of vigilance, learning and the neuromodulatory systems. Exp. Brain Res. 153, 554–572 (2003).

    Article  PubMed  Google Scholar 

  8. Metherate, R. et al. Spectral integration in auditory cortex: mechanisms and modulation. Hear. Res. 206, 146–158 (2005).

    Article  PubMed  Google Scholar 

  9. Bruno, R.M. & Sakmann, B. Cortex is driven by weak but synchronously active thalamocortical synapses. Science 312, 1622–1627 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Alonso, J.M., Usrey, W.M. & Reid, R.C. Precisely correlated firing in cells of the lateral geniculate nucleus. Nature 383, 815–819 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. McCormick, D.A. & Prince, D.A. Actions of acetylcholine in the guinea-pig and cat medial and lateral geniculate nuclei, in vitro. J. Physiol. (Lond.) 392, 147–165 (1987).

    Article  CAS  Google Scholar 

  12. Curro Dossi, R., Pare, D. & Steriade, M. Short-lasting nicotinic and long-lasting muscarinic depolarizing responses of thalamocortical neurons to stimulation of mesopontine cholinergic nuclei. J. Neurophysiol. 65, 393–406 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Roerig, B., Nelson, D.A. & Katz, L.C. Fast synaptic signaling by nicotinic acetylcholine and serotonin 5--HT3 receptors in developing visual cortex. J. Neurosci. 17, 8353–8362 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chu, Z.G., Zhou, F.M. & Hablitz, J.J. Nicotinic acetylcholine receptor-mediated synaptic potentials in rat neocortex. Brain Res. 887, 399–405 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Alkondon, M., Pereira, E.F., Eisenberg, H.M. & Albuquerque, E.X. Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks. J. Neurosci. 20, 66–75 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gil, Z., Connors, B.W. & Amitai, Y. Differential regulation of neocortical synapses by neuromodulators and activity. Neuron 19, 679–686 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Lambe, E.K., Picciotto, M.R. & Aghajanian, G.K. Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28, 216–225 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Ding, Y.S. et al. 6-[18F]Fluoro-A-85380, a new PET tracer for the nicotinic acetylcholine receptor: studies in the human brain and in vivo demonstration of specific binding in white matter. Synapse 53, 184–189 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Cruikshank, S.J., Rose, H.J. & Metherate, R. Auditory thalamocortical synaptic transmission in vitro. J. Neurophysiol. 87, 361–384 (2002).

    Article  PubMed  Google Scholar 

  20. Rose, H.J. & Metherate, R. Auditory thalamocortical transmission is reliable and temporally precise. J. Neurophysiol. 94, 2019–2030 (2005).

    Article  PubMed  Google Scholar 

  21. Léna, C., Changeux, J.P. & Mulle, C. Evidence for “preterminal” nicotinic receptors on GABAergic axons in the rat interpeduncular nucleus. J. Neurosci. 13, 2680–2688 (1993).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Alle, H. & Geiger, J.R. Combined analog and action potential coding in hippocampal mossy fibers. Science 311, 1290–1293 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Shu, Y., Hasenstaub, A., Duque, A., Yu, Y. & McCormick, D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential. Nature 441, 761–765 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Armett, C.J. & Ritchie, J.M. The action of acetylcholine and some related substances on conduction in mammalian non-myelinated nerve fibres. J. Physiol. (Lond.) 155, 372–384 (1961).

    Article  CAS  Google Scholar 

  25. Brown, D.A., Docherty, R.J. & Halliwell, J.V. The action of cholinomimetic substances on impulse conduction in the habenulointerpeduncular pathway of the rat in vitro. J. Physiol. (Lond.) 353, 101–109 (1984).

    Article  CAS  Google Scholar 

  26. Lang, P.M. et al. Characterization of neuronal nicotinic acetylcholine receptors in the membrane of unmyelinated human C-fiber axons by in vitro studies. J. Neurophysiol. 90, 3295–3303 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, C.L., Verbny, Y., Malek, S.A., Stys, P.K. & Chiu, S.Y. Nicotinic acetylcholine receptors in mouse and rat optic nerves. J. Neurophysiol. 91, 1025–1035 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Waxman, S.G. & Ritchie, J.M. Molecular dissection of the myelinated axon. Ann. Neurol. 33, 121–136 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Rawlins, F.A. & Villegas, J. Autoradiographic localization of acetylcholine receptors in the Schwann cell membrane of the squid nerve fiber. J. Cell Biol. 77, 371–376 (1978).

    Article  CAS  PubMed  Google Scholar 

  30. Pidoplichko, V.I., DeBiasi, M., Williams, J.T. & Dani, J.A. Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390, 401–404 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Hashikawa, T., Molinari, M., Rausell, E. & Jones, E.G. Patchy and laminar terminations of medial geniculate axons in monkey auditory cortex. J. Comp. Neurol. 362, 195–208 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Huang, C.L. & Winer, J.A. Auditory thalamocortical projections in the cat: laminar and areal patterns of input. J. Comp. Neurol. 427, 302–331 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Sarter, M. & Bruno, J.P. Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents. Neuroscience 95, 933–952 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Mesulam, M.M., Mufson, E.J., Wainer, B.H. & Levey, A.I. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10, 1185–1201 (1983).

    Article  CAS  PubMed  Google Scholar 

  35. Lan, C.T., Shieh, J.Y., Wen, C.Y., Tan, C.K. & Ling, E.A. Ultrastructural localization of acetylcholinesterase and choline acetyltransferase in oligodendrocytes, glioblasts and vascular endothelial cells in the external cuneate nucleus of the gerbil. Anat. Embryol. (Berl.) 194, 177–185 (1996).

    Article  CAS  Google Scholar 

  36. Wessler, I. et al. Mammalian glial cells in culture synthesize acetylcholine. Naunyn Schmiedebergs Arch. Pharmacol. 356, 694–697 (1997).

    CAS  Google Scholar 

  37. Harkrider, A.W. & Champlin, C.A. Acute effect of nicotine on non-smokers: II. MLRs and 40-Hz responses. Hear. Res. 160, 89–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Domino, E.F. Effects of tobacco smoking on electroencephalographic, auditory evoked and event related potentials. Brain Cogn. 53, 66–74 (2003).

    Article  PubMed  Google Scholar 

  39. Liang, K. et al. Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats. Eur. J. Neurosci. 24, 857–866 (2006).

    Article  PubMed  Google Scholar 

  40. Friedman, J., Horvath, T. & Meares, R. Tobacco smoking and a 'stimulus barrier'. Nature 248, 455–456 (1974).

    Article  CAS  PubMed  Google Scholar 

  41. Knott, V.J. Tobacco effects on cortical evoked potentials to distracting stimuli. Neuropsychobiology 13, 74–80 (1985).

    Article  CAS  PubMed  Google Scholar 

  42. Raastad, M., Storm, J.F. & Andersen, P. Putative single quantum and single fibre excitatory postsynaptic currents show similar amplitude range and variability in rat hippocampal slices. Eur. J. Neurosci. 4, 113–117 (1992).

    Article  PubMed  Google Scholar 

  43. Allen, C. & Stevens, C.F. An evaluation of causes for unreliability of synaptic transmission. Proc. Natl. Acad. Sci. USA 91, 10380–10383 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dobrunz, L.E. & Stevens, C.F. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18, 995–1008 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    Article  CAS  Google Scholar 

  46. Clements, J.D. & Bekkers, J.M. Detection of spontaneous synaptic events with an optimally scaled template. Biophys. J. 73, 220–229 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. White, J.A., Rubinstein, J.T. & Kay, A.R. Channel noise in neurons. Trends Neurosci. 23, 131–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Müller-Preuss, P. & Mitzdorf, U. Functional anatomy of the inferior colliculus and the auditory cortex: current source density analyses of click-evoked potentials. Hear. Res. 16, 133–142 (1984).

    Article  PubMed  Google Scholar 

  49. Kaur, S., Rose, H.J., Lazar, R., Liang, K. & Metherate, R. Spectral integration in primary auditory cortex: laminar processing of afferent input, in vivo and in vitro. Neuroscience 134, 1033–1045 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Raastad for technical advice on axon spike recordings, T.J. Carew for comments on an earlier version of manuscript and H.J. Mun and Y. Hu for technical assistance. Supported by US National Institutes of Health grants (DC02967 and DA12929 to R.M., and DC08204 to H.K.).

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H.K. conducted the in vitro and in vivo experiments and data analysis. R.L. contributed to the in vivo experiments and data analysis. R.M. supervised the project. H.K. and R.M. co-wrote the manuscript.

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Correspondence to Raju Metherate.

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The authors declare no competing financial interests.

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Kawai, H., Lazar, R. & Metherate, R. Nicotinic control of axon excitability regulates thalamocortical transmission. Nat Neurosci 10, 1168–1175 (2007). https://doi.org/10.1038/nn1956

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