Abstract
Detecting and utilizing salience information are essential for organisms to prioritize behaviorally relevant stimuli. While the prefrontal cortex is critical for cognition and learning, how it leverages salience information remains unclear. We report that chandelier cells (ChCs) in the medial prefrontal cortex (mPFC), a unique GABAergic interneuron, encode salience information and influence learning. Using cell-type-specific calcium signal recording in male mice, we demonstrate that ChCs respond robustly to stimuli across modalities, with responses dependent on stimulus salience, as determined by novelty and intensity. Circuit-specific manipulations reveal that ChC salience coding is attributable to synaptic inputs from the anterior insular cortex and paraventricular thalamus. Furthermore, ChCs acquire salience-coding property for behaviorally relevant stimuli through associative learning. Notably, bidirectional manipulations of ChC-mediated salience detection correspondingly led to improved or impaired associative learning. Together, these findings establish mPFC ChCs as a key circuit element for processing salience information to shape learning and behavior.
Data availability
The data generated in this study are provided in the Supplementary Information and the Source Data file. Source data are provided with this paper.
Code availability
Scripts used to process the data are available at: https://doi.org/10.5281/zenodo.1807319261.
References
Knudsen, E. I. Fundamental components of attention. Annu. Rev. Neurosci. 30, 57–78 (2007).
Fecteau, J. H. & Munoz, D. P. Salience, relevance, and firing: a priority map for target selection. Trends Cogn. Sci. 10, 382–390 (2006).
Uddin, L. Q. Salience processing and insular cortical function and dysfunction. Nat. Rev. Neurosci. 16, 55–61 (2015).
Ghazizadeh, A., Griggs, W. & Hikosaka, O. Ecological origins of object salience: reward, uncertainty, aversiveness, and novelty. Front. Neurosci. 10, 378 (2016).
Menon, V. Salience network. In Brain Mapping: An Encyclopedic Reference (ed. Toga, A. W.). Vol. 5, 598–599 (Elsevier Inc, 2015).
Kapur, S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am. J. Psychiatry 160, 13–23 (2003).
White, T. P., Joseph, V., Francis, S. T. & Liddle, P. F. Aberrant salience network (bilateral insula and anterior cingulate cortex) connectivity during information processing in schizophrenia. Schizophr. Res. 123, 105–115 (2010).
Lawson, R. P., Rees, G. & Friston, K. J. An aberrant precision account of autism. Front Hum. Neurosci. 8, 302 (2014).
Uddin, L. Q. & Menon, V. The anterior insula in autism: under-connected and under-examined. Neurosci. Biobehav. Rev. 33, 1198–1203 (2009).
Menon, V. & Uddin, L. Q. Saliency, switching, attention and control: a network model of insula function. Brain Struct. Funct. 214, 655–667 (2010).
Wang, F. et al. Salience processing by glutamatergic neurons in the ventral pallidum. Sci. Bull. 65, 389–401 (2019).
Zhu, Y. et al. Dynamic salience processing in paraventricular thalamus gates associative learning. Science 362, 423–429 (2018).
Seeley, W. W. et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J. Neurosci. 27, 2349–2356 (2007).
Carlén, M. What constitutes the prefrontal cortex?. Science 358, 478–482 (2017).
Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202 (2001).
Fishell, G. & Kepecs, A. Interneuron types as attractors and controllers. Annu. Rev. Neurosci. 43, 1–30 (2020).
Huang, Z. J. & Paul, A. The diversity of GABAergic neurons and neural communication elements. Nat. Rev. Neurosci. 20, 563–572 (2019).
Viney, T. J. et al. Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo. Nat. Neurosci. 16, 1802–1811 (2013).
Buzsáki, G. & Schomburg, E. W. What does gamma coherence tell us about inter-regional neural communication?. Nat. Neurosci. 18, 484–489 (2015).
Somogyi, P. A specific ‘axo-axonal’ interneuron in the visual cortex of the rat. Brain Res. 136, 345–350 (1977).
Taniguchi, H., Lu, J. & Huang, Z. J. The spatial and temporal origin of chandelier cells in mouse neocortex. Science 339, 70–74 (2013).
Lu, J. et al. Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells. Nat. Neurosci. 20, 1377–1383 (2017).
Somogyi, P. et al. Identified axo-axonic cells are immunoreactive for GABA in the hippocampus and visual cortex of the cat. Brain Res. 332, 143–149 (1985).
DeFelipe, J., Hendry, S. H., Jones, E. G. & Schmechel, D. Variability in the terminations of GABAergic chandelier cell axons on initial segments of pyramidal cell axons in the monkey sensory-motor cortex. J. Comp. Neurol. 231, 364–384 (1985).
Crick, F. H. C. & Asanuma, C. Certain Aspects of the Anatomy and Physiology of the Cerebral Cortex. in Parallel Distributed Processing: Explorations in the Microstructure of Cognition(eds. James L. McClelland, David E. Rumelhart, PDP Research Group), Vol. 2: Psychological and Biological Models. 333–371 (MIT Press, 1986).
Inda, M. C., Defelipe, J. & Muñoz, A. The distribution of chandelier cell axon terminals that express the GABA plasma membrane transporter GAT-1 in the human neocortex. Cereb. Cortex 17, 2060–2071 (2007).
Raudales, R. et al. Specific and comprehensive genetic targeting reveals brain-wide distribution and synaptic input patterns of GABAergic axo-axonic interneurons. Elife 13, RP93481 (2024).
Woo, T. U., Whitehead, R. E., Melchitzky, D. S. & Lewis, D. A. A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc. Natl. Acad. Sci. USA 95, 5341–5346 (1998).
Ariza, J., Rogers, H., Hashemi, E., Noctor, S. C. & Martínez-Cerdeño, V. The number of chandelier and basket cells are differentially decreased in prefrontal cortex in autism. Cereb. Cortex 28, 411–420 (2018).
Woodruff, A. & Yuste, R. Of mice and men, and chandeliers. PLoS Biol. 6, e243 (2008).
Dudok, B. et al. Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior. Neuron 109, 3838–3850.e3838 (2021).
Zhao, R. et al. Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally. Sci. Adv. 10, eadk4331 (2024).
Cummings, K. A. & Clem, R. L. Prefrontal somatostatin interneurons encode fear memory. Nat. Neurosci. 23, 61–74 (2020).
Kim, D. et al. Distinct roles of parvalbumin- and somatostatin-expressing interneurons in working memory. Neuron 92, 902–915 (2016).
Schneider-Mizell, C. M. et al. Structure and function of axo-axonic inhibition. eLife 10, e73783 (2021).
Jung, K. et al. An adaptive behavioral control motif mediated by cortical axo-axonic inhibition. Nat. Neurosci. 26, 1379–1393 (2023).
Seeley, W. W. The salience network: a neural system for perceiving and responding to homeostatic demands. J. Neurosci. 39, 9878–9882 (2019).
Ovsepian, S. V. et al. Neurobiology and therapeutic applications of neurotoxins targeting transmitter release. Pharm. Ther. 193, 135–155 (2019).
Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).
Chuong, A. S. et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat. Neurosci. 17, 1123–1129 (2014).
Mackintosh, N. J. A theory of attention: variations in the associability of stimuli with reinforcement. Psychol. Rev. 82, 276–298 (1975).
Gilmartin, M. R. & Helmstetter, F. J. Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. Learn Mem. 17, 289–296 (2010).
Gilmartin, M. R., Balderston, N. L. & Helmstetter, F. J. Prefrontal cortical regulation of fear learning. Trends Neurosci. 37, 455–464 (2014).
Otis, J. M. et al. Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature 543, 103–107 (2017).
Seignette, K. et al. Experience shapes chandelier cell function and structure in the visual cortex. eLife 12, RP91153 (2024).
Dahl, M. J., Mather, M. & Werkle-Bergner, M. Noradrenergic modulation of rhythmic neural activity shapes selective attention. Trends Cogn. Sci. 26, 38–52 (2022).
Winton-Brown, T. T., Fusar-Poli, P., Ungless, M. A. & Howes, O. D. Dopaminergic basis of salience dysregulation in psychosis. Trends Neurosci. 37, 85–94 (2014).
Do-Monte, F. H., Minier-Toribio, A., Quiñones-Laracuente, K., Medina-Colón, E. M. & Quirk, G. J. Thalamic regulation of sucrose seeking during unexpected reward omission. Neuron 94, 388–400.e384 (2017).
Vollmer, K. M. et al. An opioid-gated thalamoaccumbal circuit for the suppression of reward seeking in mice. Nat. Commun. 13, 6865 (2022).
Paniccia, J. E. et al. Restoration of a paraventricular thalamo-accumbal behavioral suppression circuit prevents reinstatement of heroin seeking. Neuron 112, 772–785.e779 (2024).
Pi, H.-J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013).
Malik, R., Li, Y., Schamiloglu, S. & Sohal, V. S. Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition. Cell 185, 1602–1617.e1617 (2022).
Paquelet, G. E. et al. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron 110, 2664–2679.e2668 (2022).
Courtin, J. et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014).
Pan-Vazquez, A., Wefelmeyer, W., Gonzalez Sabater, V., Neves, G. & Burrone, J. Activity-dependent plasticity of axo-axonic synapses at the axon initial segment. Neuron 106, 265–276.e6 (2020).
Wang, B. S. et al. Retinal and callosal activity-dependent chandelier cell elimination shapes binocularity in primary visual cortex. Neuron 109, 502–515.e507 (2021).
Grant, R. I. et al. Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seeking. Elife 10, e65764 (2021).
Fernandez-Leon, J. A. et al. Neural correlates and determinants of approach-avoidance conflict in the prelimbic prefrontal cortex. Elife 10, e74950 (2021).
Do-Monte, F. H., Quiñones-Laracuente, K. & Quirk, G. J. A temporal shift in the circuits mediating retrieval of fear memory. Nature 519, 460–463 (2015).
Abe, K. et al. Functional diversity of dopamine axons in prefrontal cortex during classical conditioning. Elife 12, RP91136 (2024).
Zhang, K. Analysis code for chandelier cell salience encoding. Zenodo https://doi.org/10.5281/zenodo.18073192876 (2025).
Acknowledgements
We thank Ninglong Xu and members of the Lu laboratory for helpful comments on the manuscript. We thank Wen Fang for head fixation stimulation experiment and Ninglong Xu for head-plate. The mouse and behavioral paradigm illustrations in Figs. 1–8 and Supplementary Figs. 2, 5, 6, 7, 8, 10, 11, 12, 15, 16, and 17 were adapted from SciDraw.io (Andrew Hardaway, Federico Claudi, and Alex Harston) under a CC-BY license. We thank Federico Claudi and SciDraw.io for providing the original illustrations. This work was supported by National Science and Technology Innovation 2030 Major Projects of China STI2030-Major Projects (2021ZD0202801 to J.L.), National Natural Science Foundation of China (31972903 to J.L., 32371073 to J.L., 82071450 to Y.T., 32000681 to Y.T., 31970971 to M.H.), National Science and Technology Innovation 2030 Major Projects of China STI2030-Major Projects (2022ZD0206500 to M.H.), Shanghai Science and Technology Innovation Action Plan (22YF1421000 to D.H.).
Author information
Authors and Affiliations
Contributions
Y.T. and J.L. conceived the project. K.Z., M.S., and Q.K. performed most of the experiments. M.L., B.R., R.Z., D.H., Q.Y., T.X., M.H., and Z.J.H. helped interpret results. K.Z., Y.T., and J.L. wrote the original draft of the paper. All of the authors provided comments on and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Kanghoon Jung and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Zhang, K., Shao, M., Kong, Q. et al. Prefrontal chandelier cells encode stimulus salience to influence learning in male mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68959-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-68959-3
