Heterogeneity of phasic cholinergic signaling in neocortical neurons
Abstract
Acetylcholine (ACh) is a neurotransmitter critical for normal cognition. Here we demonstrate heterogeneity of cholinergic signaling in neocortical neurons in the rat prefrontal, somatosensory, and visual cortex. Focal ACh application (100 muM) inhibited layer 5 pyramidal neurons in all cortical areas via activation of an apamin-sensitive SK-type calcium-activated potassium conductance. Cholinergic inhibition was most robust in prefrontal layer 5 neurons, where it relies on the same signal transduction mechanism (M1-like receptors, IP(3)-dependent calcium release, and SK-channels) as exists in somatosensory pyramidal neurons. Pyramidal neurons in layer 2/3 were less responsive to ACh, but substantial apamin-sensitive inhibitory responses occurred in deep layer 3 neurons of the visual cortex. ACh was only inhibitory when presented near the somata of layer 5 pyramidal neurons, where repetitive ACh applications generated discrete inhibitory events at frequencies of up to approximately 0.5 Hz. Fast-spiking (FS) nonpyramidal neurons in all cortical areas were unresponsive to ACh. When applied to non-FS interneurons in layers 2/3 and 5, ACh generated mecamylamine-sensitive nicotinic responses (38% of cells), apamin-insensitive hyperpolarizing responses, with or without initial nicotinic depolarization (7% of neurons), or no response at all (55% of cells). Responses in interneurons were similar across cortical layers and regions but were correlated with cellular physiology and the expression of biochemical markers associated with different classes of nonpyramidal neurons. Finally, ACh generated nicotinic responses in all layer 1 neurons tested. These data demonstrate that phasic cholinergic input can directly inhibit projection neurons throughout the cortex while sculpting intracortical processing, especially in superficial layers.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The slow depolarization is mediated by M1 muscarinic receptor-mediated closure of M-type (KCNQ) potassium channels in pyramidal neurons enhancing their excitability and reducing their spike frequency adaptation.
“The slow depolarization is mediated by M1 mAChR-mediated closure of M-type (KCNQ) potassium channels in pyramidal neurons (Delmas and Brown, 2005) enhancing their excitability and reducing their spike frequency adaptation (Gulledge et al., 2007; Hasselmo and Giocomo, 2006).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Gulledge et al., 2007
Activation of M1 muscarinic acetylcholine receptors hyperpolarizes pyramidal neurons via a mechanism dependent on fully-loaded internal calcium stores that occurs more quickly than the closure of M-type potassium channels.
“Furthermore, activation of M1 mAChRs hyperpolarizes pyramidal neurons via a mechanism dependent on fully-loaded internal calcium stores that occurs more quickly than the closure of M-type potassium channels (Gulledge et al., 2007; Gulledge and Stuart, 2005).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Gulledge et al., 2007
Cites
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954 · see citing works
GABAergic cell subtypes and their synaptic connections in rat frontal cortex
Kawaguchi, Y. (1997) · Cerebral Cortex · doi:10.1093/cercor/7.6.476 · Cited by 1,416 · see citing works
Self-citationNucleus basalis and thalamic control of neocortical activity in the freely moving rat
Buzsáki, G., Bickford, R. G., Ponomareff, G., Thal, L. J., Mandel, R. J., & Gage, F. H. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-11-04007.1988 · Cited by 1,039 · see citing works
The mechanism of excitation by acetylcholine in the cerebral cortex
Krnjević, K., Pumain, R., & Renaud, L. P. (1971) · The Journal of Physiology · doi:10.1113/jphysiol.1971.sp009467 · Cited by 708 · see citing works
Determinants of Voltage Attenuation in Neocortical Pyramidal Neuron Dendrites
Stuart, G. J., & Spruston, N. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-10-03501.1998 · Cited by 527 · see citing works
Self-citationHeterogeneity in the pyramidal network of the medial prefrontal cortex
Wang, Y., Markram, H., Goodman, P. H., Berger, T. K., Ma, J., & Goldman-Rakic, P. S. (2006) · Nature Neuroscience · doi:10.1038/nn1670 · Cited by 503 · see citing works
Mechanisms of action of acetylcholine in the guinea‐pig cerebral cortex in vitro.
McCormick, D. A., & Prince, D. A. (1986) · The Journal of Physiology · doi:10.1113/jphysiol.1986.sp016112 · Cited by 499 · see citing works
Cholinergic Basal Forebrain Neurons Burst with Theta during Waking and Paradoxical Sleep
Lee, M., Hassani, O. K., Alonso, Á., & Jones, B. E. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0178-05.2005 · Cited by 439 · see citing works
Cholinergic Switching Within Neocortical Inhibitory Networks
Xiang, Z., Huguenard, J. R., & Prince, D. A. (1998) · Science · doi:10.1126/science.281.5379.985 · Cited by 438 · see citing works
Diffuse transmission by acetylcholine in the CNS
Descarries, L., Gisiger, V., & Steriade, M. (1997) · Progress in Neurobiology · doi:10.1016/s0301-0082(97)00050-6 · Cited by 406 · see citing works
Kawaguchi, Y., & Kondo, S. (2002) · Journal of Neurocytology · doi:10.1023/a:1024126110356 · Cited by 395 · see citing works
Self-citationClassification of fusiform neocortical interneurons based on unsupervised clustering
Cauli, B., Porter, J. T., Tsuzuki, K., Lambolez, B., Rossier, J., Quenet, B., & Audinat, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.11.6144 · Cited by 316 · see citing works
Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex
Jones, B. E. (2004) · Progress in brain research · doi:10.1016/s0079-6123(03)45011-5 · Cited by 304 · see citing works
Two types of muscarinic response to acetylcholine in mammalian cortical neurons.
McCormick, D. A., & Prince, D. A. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.18.6344 · Cited by 302 · see citing works
Recurrent Connection Patterns of Corticostriatal Pyramidal Cells in Frontal Cortex
Morishima, M., & Kawaguchi, Y. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0252-06.2006 · Cited by 273 · see citing works
Self-citationSelective Excitation of Subtypes of Neocortical Interneurons by Nicotinic Receptors
Porter, J. T., Cauli, B., Tsuzuki, K., Lambolez, B., Rossier, J., & Audinat, E. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-13-05228.1999 · Cited by 262 · see citing works
Selective Cholinergic Modulation of Cortical GABAergic Cell Subtypes
Kawaguchi, Y. (1997) · Journal of Neurophysiology · doi:10.1152/jn.1997.78.3.1743 · Cited by 250 · see citing works
Self-citationSailer, C. A., Hu, H., Kaufmann, W. A., Trieb, M., Schwarzer, C., Storm, J. F., & Knaus, H. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-22-09698.2002 · Cited by 202 · see citing works
Changes in Acetylcholine Extracellular Levels During Cognitive Processes: Table 1.Preprint
Pepeu, G., & Giovannini, M. G. (2004) · Learning & Memory · doi:10.1101/lm.68104 · Cited by 193 · see citing works
Muscarinic Activation of a Voltage-Dependent Cation Nonselective Current in Rat Association Cortex
Haj‐Dahmane, S., & Andrade, R. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-12-03848.1996 · Cited by 187 · see citing works
Cholinergic Inhibition of Neocortical Pyramidal Neurons
Gulledge, A. T., & Stuart, G. J. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2697-05.2005 · Cited by 182 · see citing works
Self-citationThe role of basal forebrain neurons in tonic and phasic activation of the cerebral cortex
Détári, L., Rasmusson, D. D., & Semba, K. (1999) · Progress in Neurobiology · doi:10.1016/s0301-0082(98)00084-7 · Cited by 151 · see citing works
Turrini, P., Casu, M. A., Wong, T. P., De Koninck, Y., Ribeiro-da-Silva, A., & Cuello, A. C. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00172-5 · Cited by 135 · see citing works
Two Types of Nicotinic Receptors Mediate an Excitation of Neocortical Layer I Interneurons
Christophe, E., Roebuck, A., Staiger, J. F., Lavery, D. J., Charpak, S., & Audinat, E. (2002) · Journal of Neurophysiology · doi:10.1152/jn.2002.88.3.1318 · Cited by 130 · see citing works
Cell excitation enhances muscarinic cholinergic responses in rat association cortex
Andrade, R. (1991) · Brain Research · doi:10.1016/0006-8993(91)91109-e · Cited by 109 · see citing works
Gulledge, A. T., & Stuart, G. J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-36-11363.2003 · Cited by 99 · see citing works
Self-citationCholinergic synaptic circuitry in the macaque prefrontal cortex
Mrzijak, L., Pappy, M., Léránth, C., & Goldman, P. S. (1995) · The Journal of Comparative Neurology · doi:10.1002/cne.903570409 · Cited by 92 · see citing works
Cholinergic synapses in human cerebral cortex: an ultrastructural study in serial sections
Smiley, J. F., Morrell, F., & Mesulam, M. M. (1997) · Experimental Neurology · doi:10.1006/exnr.1997.6413 · Cited by 79 · see citing works
Cholinergic inhibition in the cerebral cortex
Phillis, J. W., & York, D. H. (1967) · Brain Research · doi:10.1016/0006-8993(67)90025-x · Cited by 78 · see citing works
Heterogeneous Actions of Serotonin on Interneurons in Rat Visual Cortex
Xiang, Z., & Prince, D. A. (2003) · Journal of Neurophysiology · doi:10.1152/jn.00533.2002 · Cited by 67 · see citing works
Ultrastructural features of the acetylcholine innervation in the developing parietal cortex of rat
Mechawar, N., Watkins, K. C., & Descarries, L. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10114 · Cited by 58 · see citing works
Vinson, P. N., & Justice, J. B. (1997) · Journal of Neuroscience Methods · doi:10.1016/s0165-0270(96)02213-3 · Cited by 58 · see citing works
Casu, M. A. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.3.329 · Cited by 55 · see citing works
Yamada, S., Takechi, H., Kanchiku, I., Kita, T., & Kato, N. (2004) · Journal of Neurophysiology · doi:10.1152/jn.01049.2003 · Cited by 44 · see citing works
Electrophysiological characterization of cloned m1 muscarinic receptors expressed in A9 L cells.
Jones, S. V. P., Barker, J. L., Bonner, T. I., et al. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.11.4056 · Cited by 38 · see citing works
Wang, Y. Z., Gu, Q., Mao, F., Haugland, R., & Cynader, M. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-07-04147.1994 · Cited by 24 · see citing works
Excitatory-inhibitory balance : synapses, circuits, systems
Hensch, T. K., & Fagiolini, M. (2004) · Medical Entomology and Zoology · Cited by 22 · see citing works
Atropine-sensitive and -insensitive components of the somatosensory evoked potential
Dancause, N., Dykes, R. W., Miasnikov, A. A., & Agueev, V. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02630-0 · Cited by 9 · see citing works
Local Circuit Neurons in the Frontal Cortico-Striatal System
Kawaguchi, Y. (2003) · Springer eBooks · doi:10.1007/978-1-4615-0039-1_9 · Cited by 7 · see citing works
Self-citationEffect of Background Activity on the Action of Acetylcholine on the Electrical Activity of the Brain
Crossland, J., & MITCHELL, J. F. (1955) · Nature · doi:10.1038/175121a0 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex
The Petilla Interneuron Nomenclature Group (PING) (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2402 · Cited by 1,491 · see citing works
Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior
Picciotto, M. R., Higley, M. J., & Mineur, Y. S. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.036 · Cited by 1,404 · see citing works
Membrane potential dynamics of GABAergic neurons in the barrel cortex of behaving mice
Gentet, L. J., Avermann, M., Matyas, F., Staiger, J. F., & Petersen, C. C. H. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.006 · Cited by 429 · see citing works
Astrocyte Calcium Signaling Transforms Cholinergic Modulation to Cortical Plasticity <i>In Vivo</i>
Takata, N., Mishima, T., Hisatsune, C., Nagai, T., Ebisui, E., Mikoshiba, K., & Hirase, H. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5289-11.2011 · Cited by 382 · see citing works
Gain Modulation by Nicotine in Macaque V1
Disney, A. A., Aoki, C., & Hawken, M. J. (2007) · Neuron · doi:10.1016/j.neuron.2007.09.034 · Cited by 331 · see citing works
Mechanisms underlying gain modulation in the cortex
Ferguson, K. A., & Cardin, J. A. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0253-y · Cited by 327 · see citing works
Goriounova, N. A., & Mansvelder, H. D. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a012120 · Cited by 307 · see citing works
“Increased inhibition through activation of nAChRs expressed by interneurons has been found in many different brain regions (Jones and Yakel 1997; Xiang et al. 1998; McQuiston and Madison 1999; Alkondon et al. 2000; Ji and Dani 2000; Mansvelder et al. 2002; Gulledge et al. 2007).”
BackgroundClassification of NPY-Expressing Neocortical Interneurons
Karagiannis, A., Gallopin, T., Dávid, C., Battaglia, D., Geoffroy, H., Rossier, J., Hillman, E. M. C., Staiger, J. F., & Cauli, B. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0058-09.2009 · Cited by 256 · see citing works
Couey, J. J., Meredith, R. M., Spijker, S., Poorthuis, R. B., Smit, A. B., Brussaard, A. B., & Mansvelder, H. D. (2007) · Neuron · doi:10.1016/j.neuron.2007.03.006 · Cited by 253 · see citing works
Uematsu, M., Hirai, Y., Karube, F., Ebihara, S., Kato, M., Abe, K., Obata, K., Yoshida, S., Hirabayashi, M., Yanagawa, Y., et al. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhm056 · Cited by 232 · see citing works
Self-citationCholinergic signals in mouse barrel cortex during active whisker sensing
Eggermann, E., Kremer, Y., Crochet, S., & Petersen, C. C. H. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.005 · Cited by 234 · see citing works
Kruglikov, I., & Rudy, B. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.024 · Cited by 209 · see citing works
Neuromodulation by acetylcholine: examples from schizophrenia and depression
Higley, M. J., & Picciotto, M. R. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.06.004 · Cited by 184 · see citing works
Pedarzani, P., & Stocker, M. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8216-x · Cited by 173 · see citing works
GABA interneurons mediate the rapid antidepressant-like effects of scopolamine
Wohleb, E. S., Wu, M., Gerhard, D. M., Taylor, S. R., Picciotto, M. R., Alreja, M., & Duman, R. S. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85033 · Cited by 144 · see citing works
Arroyo, S., Bennett, C., Aziz, D., Brown, S. P., & Hestrin, S. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0115-12.2012 · Cited by 138 · see citing works
Chrna2-Martinotti cells synchronize layer 5 type A pyramidal cells via rebound excitation
Hilscher, M. M., Leão, R. N., Edwards, S. J., Leão, K. E., & Kullander, K. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2001392 · Cited by 118 · see citing works
Fogaça, M. V., Wu, M., Li, C., Li, X.-Y., Picciotto, M. R., & Duman, R. S. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00916-y · Cited by 129 · see citing works
Cholinergic control of GABA release: emerging parallels between neocortex and hippocampus
Lawrence, J. J. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.03.008 · Cited by 115 · see citing works
Disney, A. A., & Aoki, C. (2008) · Journal of Comparative Neurology · doi:10.1002/cne.21616 · Cited by 109 · see citing works
Nicotinic actions on neuronal networks for cognition: General principles and long-term consequences
Poorthuis, R. B., Goriounova, N. A., Couey, J. J., & Mansvelder, H. D. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.04.031 · Cited by 102 · see citing works
Revisiting enigmatic cortical calretinin-expressing interneurons
Cauli, B., Zhou, X., Tricoire, L., Toussay, X., & Staiger, J. F. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00052 · Cited by 86 · see citing works
Goriounova, N. A., & Mansvelder, H. D. (2012) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2012.00003 · Cited by 65 · see citing works
Cholinergic suppression of visual responses in primate V1 is mediated by GABAergic inhibition
Disney, A. A., Aoki, C., & Hawken, M. J. (2012) · Journal of Neurophysiology · doi:10.1152/jn.00188.2012 · Cited by 57 · see citing works
Dasgupta, R., Seibt, F., & Beierlein, M. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.0566-18.2018 · Cited by 47 · see citing works
Lopes Aguiar, C., Romcy-Pereira, R. N., Escorsim Szawka, R., Galvis-Alonso, O. Y., Anselmo-Franci, J. A., & Pereira Leite, J. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.02.040 · Cited by 42 · see citing works
Disney, A. A., & Reynolds, J. H. (2014) · Journal of Comparative Neurology · doi:10.1002/cne.23456 · Cited by 40 · see citing works
“In contrast, previous physiological data suggest that PV-ir neurons in the neocortex of rats rarely express pirenzepine-sensitive muscarinic AChRs (Gulledge et al., 2007; Kawaguchi, 1997; Kruglikov and Rudy, 2008).”
BackgroundResultInfluentialDisney, A. A., Alasady, H. A., & Reynolds, J. H. (2014) · Brain and Behavior · doi:10.1002/brb3.225 · Cited by 28 · see citing works
Immunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex
Oda, S., Tsuneoka, Y., Yoshida, S., Adachi‐Akahane, S., Ito, M., Kuroda, M., & Funato, H. (2018) · Journal of Comparative Neurology · doi:10.1002/cne.24409 · Cited by 27 · see citing works
- Authors
- Gulledge, A. T., Park, S. B., Kawaguchi, Y., & Stuart, G. J.
- Affiliations
- National Institute for Physiological Sciences (JP)
- Venue
- Journal of Neurophysiology
- Publisher
- American Physiological Society
- Published
- 2007-03
- Volume
- 97
- Issue
- 3
- Pages
- 2215-2229
- ISSN
- 0022-3077 (ISSN-L)
- 1522-1598
- OpenAlex
- W2015061703
- Cited by
- 194
- References
- 40
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 10 · 2018: 15 · 2017: 11 · 2016: 14 · 2015: 12 · 2014: 14 · 2013: 18 · 2012: 15
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurophysiology (publishedVersion)
- PubMed (publishedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- acetylcholine, neocortical neurons, layer 5 pyramidal neurons, small conductance calcium-activated potassium channels, M1 muscarinic receptor, nicotinic acetylcholine receptors, fast-spiking interneurons, non-pyramidal neurons, prefrontal cortex, somatosensory cortex, visual cortex, cortical inhibition
- MeSH terms
- Acetylcholine, Analysis of Variance, Animals, Apamin, Calcium, Chelating Agents, Diamines, Dose-Response Relationship, Radiation, Egtazic Acid, Electric Stimulation, Membrane Potentials, Neural Inhibition, Neurons, Signal Transduction, Patch-Clamp Techniques, Cholinergic Agents, Neocortex, Rats, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
