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.

  • Article
  • Published:

Acetylcholine muscarinic M1 receptors in the rodent prefrontal cortex modulate cognitive abilities to establish social hierarchy

Neuropsychopharmacology volume 49, pages 974–982 (2024)Cite this article

Subjects

Abstract

In most social species, the attainment of social dominance is strongly affected by personality traits. Dominant individuals show better cognitive abilities, however, whether an individual’s cognition can determine its social status has remained inconclusive. We found that mice show better cognitive abilities tend to possess a higher social rank after cohousing. The dynamic release of acetylcholine (ACh) in the prelimbic cortex (PL) is correlated with mouse dominance behavior. ACh enhanced the excitability of the PL neurons via acetylcholine muscarinic M1 receptors (M1). Inhibition of M1 impaired mice cognitive performance and induced losing in social competition. Mice with M1 deficiency in the PL performed worse on cognitive behavioral tests, and exhibited lower status when re-grouped with others. Elevating ACh level in the PL of subordinate mice induced winning. These results provide direct evidence for the involvement of M1 in social hierarchy and suggest that social rank can be tuned by altering cognition through cholinergic system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Superior cognitive abilities predict mice social dominance after cohousing.
Fig. 2: The level of ACh in the PL is correlated with mouse dominance behavior in tube test.
Fig. 3: ACh enhances the excitability of the PL neurons through M1.
Fig. 4: Cognitive impairment induced lose in social competition in tube test.
Fig. 5: Elevating ACh level induced winning against previously dominant opponents through M1 the prefrontal cortex.

Similar content being viewed by others

References

  1. Sapolsky RM. The influence of social hierarchy on primate health. Science. 2005;308:648–52.

    CAS  PubMed  Google Scholar 

  2. Yeh SR, Fricke RA, Edwards DH. The effect of social experience on serotonergic modulation of the escape circuit of crayfish. Science. 1996;271:366–9.

    CAS  PubMed  Google Scholar 

  3. Rushworth MF, Kolling N, Sallet J, Mars RB. Valuation and decision-making in frontal cortex: one or many serial or parallel systems? Curr Opin Neurobiol. 2012;22:946–55.

    CAS  PubMed  Google Scholar 

  4. Mooney SJ, Peragine DE, Hathaway GA, Holmes MM. A game of thrones: neural plasticity in mammalian social hierarchies. Soc Neurosci. 2014;9:108–17.

    PubMed  Google Scholar 

  5. Sandi C, Haller J. Stress and the social brain: behavioural effects and neurobiological mechanisms. Nat Rev Neurosci. 2015;16:290–304.

    CAS  PubMed  Google Scholar 

  6. Boogert NJ, Reader SM, Laland KN. The relation between social rank, neophobia and individual learning in starlings. Anim Behav. 2006;72:1229–39.

    Google Scholar 

  7. Barnard CJ, Luo N. Acquisition of dominance status affects maze learning in mice. Behav Process. 2002;60:53–9.

    Google Scholar 

  8. Francia N, Cirulli F, Chiarotti F, Antonelli A, Aloe L, Alleva E. Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status: role of hippocampal neurotrophins. Eur J Neurosci. 2006;23:711–28.

    CAS  PubMed  Google Scholar 

  9. Pravosudov VV, Mendoza SP, Clayton NS. The relationship between dominance, corticosterone, memory, and food caching in mountain chickadees (Poecile gambeli). Hormones Behav. 2003;44:93–102.

    CAS  Google Scholar 

  10. Seyfarth RM, Cheney DL. What are big brains for? Proc Natl Acad Sci USA. 2002;99:4141–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Fernald RD. Cognitive skills needed for social hierarchies. Cold Spring Harb Symposia Quant Biol. 2014;79:229–36.

    PubMed  Google Scholar 

  12. Tibbetts EA, Pardo-Sanchez J, Weise C. The establishment and maintenance of dominance hierarchies. Philos Trans R Soc Lond Ser B, Biol Sci. 2022;377:20200450.

    Google Scholar 

  13. Reader SM, Laland KN. Social intelligence, innovation, and enhanced brain size in primates. Proc Natl Acad Sci USA. 2002;99:4436–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nicol CJ, Pope SJ. The effects of demonstrator social status and prior foraging success on social learning in laying hens. Anim Behav. 1999;57:163–71.

    CAS  PubMed  Google Scholar 

  15. Zink CF, Tong Y, Chen Q, Bassett DS, Stein JL, Meyer-Lindenberg A. Know your place: neural processing of social hierarchy in humans. Neuron. 2008;58:273–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Dulka BN, Bress KS, Grizzell JA, Cooper MA. Social dominance modulates stress-induced neural activity in medial prefrontal cortex projections to the basolateral amygdala. Neuroscience. 2018;388:274–83.

    CAS  PubMed  Google Scholar 

  17. Wang F, Zhu J, Zhu H, Zhang Q, Lin Z, Hu H. Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science. 2011;334:693–7.

    CAS  PubMed  Google Scholar 

  18. Zhou T, Zhu H, Fan Z, Wang F, Chen Y, Liang H, et al. History of winning remodels thalamo-PFC circuit to reinforce social dominance. Science. 2017;357:162–8.

    CAS  PubMed  Google Scholar 

  19. Kolb B, Buhrmann K, McDonald R, Sutherland RJ. Dissociation of the medial prefrontal, posterior parietal, and posterior temporal cortex for spatial navigation and recognition memory in the rat. Cereb cortex. 1994;4:664–80.

    CAS  PubMed  Google Scholar 

  20. Wang GW, Cai JX. Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats. Behav Brain Res. 2006;175:329–36.

    PubMed  Google Scholar 

  21. Spellman T, Rigotti M, Ahmari SE, Fusi S, Gogos JA, Gordon JA. Hippocampal-prefrontal input supports spatial encoding in working memory. Nature. 2015;522:309–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Miller EK, Freedman DJ, Wallis JD. The prefrontal cortex: categories, concepts and cognition. Philos Trans R Soc Lond Ser B Biol Sci. 2002;357:1123–36.

    Google Scholar 

  23. Abbas AI, Sundiang MJM, Henoch B, Morton MP, Bolkan SS, Park AJ, et al. Somatostatin interneurons facilitate hippocampal-prefrontal synchrony and prefrontal spatial encoding. Neuron. 2018;100:926–39e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tamura M, Spellman TJ, Rosen AM, Gogos JA, Gordon JA. Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task. Nat Commun. 2017;8:2182.

    PubMed  PubMed Central  Google Scholar 

  25. Bicks LK, Koike H, Akbarian S, Morishita H. Prefrontal cortex and social cognition in mouse and man. Front Psychol. 2015;6:1805.

    PubMed  PubMed Central  Google Scholar 

  26. Blakemore SJ. The social brain in adolescence. Nat Rev Neurosci. 2008;9:267–77.

    CAS  PubMed  Google Scholar 

  27. Xing B, Mack NR, Guo KM, Zhang YX, Ramirez B, Yang SS, et al. A subpopulation of prefrontal cortical neurons is required for social memory. Biol psychiatry. 2021;89:521–31.

    CAS  PubMed  Google Scholar 

  28. Ballinger EC, Ananth M, Talmage DA, Role LW. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron. 2016;91:1199–218.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76:116–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Shirey JK, Brady AE, Jones PJ, Davis AA, Bridges TM, Kennedy JP, et al. A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci. 2009;29:14271–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Digby GJ, Noetzel MJ, Bubser M, Utley TJ, Walker AG, Byun NE, et al. Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. J Neurosci. 2012;32:8532–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Higashino K, Ago Y, Umeki T, Hasebe S, Onaka Y, Hashimoto H, et al. Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice. Psychopharmacology. 2016;233:521–8.

    CAS  PubMed  Google Scholar 

  33. Gulledge AT, Bucci DJ, Zhang SS, Matsui M, Yeh HH. M1 receptors mediate cholinergic modulation of excitability in neocortical pyramidal neurons. J Neurosci. 2009;29:9888–902.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Williams SR, Fletcher LN. A dendritic substrate for the cholinergic control of neocortical output neurons. Neuron. 2019;101:486–99e4.

    CAS  PubMed  Google Scholar 

  35. Xing B, Mack NR, Zhang YX, McEachern EP, Gao WJ. Distinct roles for prefrontal Dopamine D1 and D2 neurons in social hierarchy. J Neurosci. 2022;42:313–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Fan Z, Zhu H, Zhou T, Wang S, Wu Y, Hu H. Using the tube test to measure social hierarchy in mice. Nat Protoc. 2019;14:819–31.

    CAS  PubMed  Google Scholar 

  37. Shen Y, Hua L, Yeh CK, Shen L, Ying M, Zhang Z, et al. Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer’s disease. Theranostics. 2020;10:11794–819.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pan L, Zheng L, Wu X, Zhu Z, Wang S, Lu Y, et al. A short period of early life oxytocin treatment rescues social behavior dysfunction via suppression of hippocampal hyperactivity in male mice. Mol Psychiatry. 2022;27:4157–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen YH, Wu JL, Hu NY, Zhuang JP, Li WP, Zhang SR, et al. Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear. J Clin Investig. 2021;131:e145692.

  40. Zhang SR, Wu JL, Chen H, Luo R, Chen WJ, Tang LJ, et al. ErbB4 knockdown in serotonergic neurons in the dorsal raphe induces anxiety-like behaviors. Neuropsychopharmacol. 2020;45:1698–706.

    Google Scholar 

  41. Jaafari Suha A, Hosseinmardi N, Janahmadi M. Spatial working memory is disparately interrelated with social status through different developmental stages in rats. Behav Brain Res. 2022;416:113547.

    PubMed  Google Scholar 

  42. Langley EJG, van Horik JO, Whiteside MA, Beardsworth CE, Madden JR. The relationship between social rank and spatial learning in pheasants, Phasianus colchicus: cause or consequence? PeerJ. 2018;6:e5738.

    PubMed  PubMed Central  Google Scholar 

  43. Langley EJG, van Horik JO, Whiteside MA, Madden JR. Group social rank is associated with performance on a spatial learning task. R Soc Open Sci. 2018;5:171475.

    PubMed  PubMed Central  Google Scholar 

  44. Sun Q, Zhang J, Li A, Yao M, Liu G, Chen S, et al. Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer’s disease. Nat Commun. 2022;13:998.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Pezze MA, Marshall HJ, Cassaday HJ. Scopolamine impairs appetitive but not aversive trace conditioning: role of the medial prefrontal cortex. J Neurosci. 2017;37:6289–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Jing M, Li Y, Zeng J, Huang P, Skirzewski M, Kljakic O, et al. An optimized acetylcholine sensor for monitoring in vivo cholinergic activity. Nat Methods. 2020;17:1139–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Noh K, Cho WH, Lee BH, Kim DW, Kim YS, Park K, et al. Cortical astrocytes modulate dominance behavior in male mice by regulating synaptic excitatory and inhibitory balance. Nat Neurosci. 2023;26:1541–54.

    CAS  PubMed  Google Scholar 

  48. Karvat G, Kimchi T. Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism. Neuropsychopharmacol. 2014;39:831–40.

    CAS  Google Scholar 

  49. Proulx E, Suri D, Heximer SP, Vaidya VA, Lambe EK. Early stress prevents the potentiation of muscarinic excitation by calcium release in adult prefrontal cortex. Biol Psychiatry. 2014;76:315–23.

    CAS  PubMed  Google Scholar 

  50. Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Investig. 2016;126:2482–94.

    PubMed  PubMed Central  Google Scholar 

  51. Zhu H, Yan H, Tang N, Li X, Pang P, Li H, et al. Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses. Nat Commun. 2017;8:1676.

    PubMed  PubMed Central  Google Scholar 

  52. Chou YJ, Ma YK, Lu YH, King JT, Tasi WS, Yang SB, et al. Potential cross-species correlations in social hierarchy and memory between mice and young children. Commun Biol. 2022;5:230.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Varholick JA, Bailoo JD, Palme R, Wurbel H. Phenotypic variability between Social Dominance Ranks in laboratory mice. Sci Rep. 2018;8:6593.

    PubMed  PubMed Central  Google Scholar 

  54. Varholick JA, Pontiggia A, Murphy E, Daniele V, Palme R, Voelkl B, et al. Social dominance hierarchy type and rank contribute to phenotypic variation within cages of laboratory mice. Sci Rep. 2019;9:13650.

    PubMed  PubMed Central  Google Scholar 

  55. Taborsky B, Oliveira RF. Social competence: an evolutionary approach. Trends Ecol Evolut. 2012;27:679–88.

    Google Scholar 

  56. Fujii N, Hihara S, Nagasaka Y, Iriki A. Social state representation in prefrontal cortex. Soc Neurosci. 2009;4:73–84.

    PubMed  Google Scholar 

  57. Friedman A, Homma D, Gibb LG, Amemori K-I, Rubin SJ, Hood AS, et al. A corticostriatal path targeting striosomes controls decision-making under conflict. Cell. 2015;161:1320–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hillman KL, Bilkey DK. Neural encoding of competitive effort in the anterior cingulate cortex. Nat Neurosci. 2012;15:1290–7.

    CAS  PubMed  Google Scholar 

  59. Holroyd CB, McClure SM. Hierarchical control over effortful behavior by rodent medial frontal cortex: a computational model. Psychol Rev. 2015;122:54–83.

    PubMed  Google Scholar 

  60. Hosokawa T, Watanabe M. Prefrontal neurons represent winning and losing during competitive video shooting games between monkeys. J Neurosci. 2012;32:7662–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Oda S, Tsuneoka Y, Yoshida S, Adachi-Akahane S, Ito M, Kuroda M, et al. Immunolocalization of muscarinic M1 receptor in the rat medial prefrontal cortex. J Comp Neurol. 2018;526:1329–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang C, Zhu H, Ni Z, Xin Q, Zhou T, Wu R, et al. Dynamics of a disinhibitory prefrontal microcircuit in controlling social competition. Neuron. 2022;110:516–31e6.

    CAS  PubMed  Google Scholar 

  63. Obermayer J, Luchicchi A, Heistek TS, de Kloet SF, Terra H, Bruinsma B, et al. Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention. Nat Commun. 2019;10:5280.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Esaki H, Deyama S, Izumi S, Katsura A, Nishikawa K, Nishitani N, et al. Varenicline enhances recognition memory via alpha7 nicotinic acetylcholine receptors in the medial prefrontal cortex in male mice. Neuropharmacology. 2023;239:109672.

  65. Esaki H, Izumi S, Fukao A, Ito S, Nishitani N, Deyama S, et al. Nicotine enhances object recognition memory via stimulating alpha4beta2 and alpha7 nicotinic acetylcholine receptors in the medial prefrontal cortex of mice. Biol Pharm Bull. 2021;44:1007–13.

    CAS  PubMed  Google Scholar 

  66. Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci. 1991;11:3218–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kurowski P, Gawlak M, Szulczyk P. Muscarinic receptor control of pyramidal neuron membrane potential in the medial prefrontal cortex (mPFC) in rats. Neuroscience. 2015;303:474–88.

    CAS  PubMed  Google Scholar 

  68. Satake T, Mitani H, Nakagome K, Kaneko K. Individual and additive effects of neuromodulators on the slow components of afterhyperpolarization currents in layer V pyramidal cells of the rat medial prefrontal cortex. Brain Res. 2008;1229:47–60.

    CAS  PubMed  Google Scholar 

  69. Zhao LX, Chen MW, Qian Y, Yang QH, Ge YH, Chen HZ, et al. M1 muscarinic receptor activation rescues beta-amyloid-induced cognitive impairment through AMPA receptor GluA1 subunit. Neuroscience. 2019;408:239–47.

    CAS  PubMed  Google Scholar 

  70. Zhao LX, Ge YH, Li JB, Xiong CH, Law PY, Xu JR, et al. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt. FASEB J. 2019;33:6622–31.

    CAS  PubMed  Google Scholar 

  71. Fan Z, Chang J, Liang Y, Zhu H, Zhang C, Zheng D, et al. Neural mechanism underlying depressive-like state associated with social status loss. Cell. 2023;186:560–76e17.

    CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from the Guangdong Basic and Applied Basic Research Foundation (2022A1515011987) to J-LW and Scientific Research Starting Foundation for High-level Talents of Meizhou People’s Hospital (KYQD202301 to W-JC, KYQD202302 to J-LW).

Author information

Authors and Affiliations

  1. Medical Research and Experimental Center, Meizhou People’s Hospital, Meizhou, 514031, China

    Wen-Jun Chen & Jian-Lin Wu

  2. Guangdong Engineering Technological Research Center of Clinical Molecular Diagnosis and Antibody Drugs, Meizhou, 514031, China

    Wen-Jun Chen & Jian-Lin Wu

  3. Department of Neurobiology, Southern Medical University, Guangzhou, 510515, China

    Hao Chen & Zi-Ming Li

  4. Orthopedic Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China

    Wei-Yuan Huang

Authors
  1. Wen-Jun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zi-Ming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei-Yuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Lin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W-JC performed the experiments, HC and Z-ML contributed to experiments, W-YH and J-LW designed the study, J-LW supervised the work. W-JC wrote manuscript with help of J-LW. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Wei-Yuan Huang or Jian-Lin Wu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, WJ., Chen, H., Li, ZM. et al. Acetylcholine muscarinic M1 receptors in the rodent prefrontal cortex modulate cognitive abilities to establish social hierarchy. Neuropsychopharmacol. 49, 974–982 (2024). https://doi.org/10.1038/s41386-023-01785-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01785-z

Search

Advanced search

Quick links