The firing of theta state-related septal cholinergic neurons disrupt hippocampal ripple oscillations via muscarinic receptors

Xiaoyu Ma, Yiyao Zhang, Lina Wang, Na Li, Edi Barkai, Xiaohui Zhang, Longnian Lin, Jiamin Xu

Research output: Contribution to journalArticlepeer-review


The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5–72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M2 or M4 receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.

Original languageEnglish
Pages (from-to)3591-3603
Number of pages13
JournalJournal of Neuroscience
Issue number18
StatePublished - 29 Apr 2020

Bibliographical note

Funding Information:
Received Aug. 5, 2019; revised Mar. 11, 2020; accepted Mar. 13, 2020. Author contributions: X.M., L.L., and J.X. designed research; X.M., Y.Z., L.W. and N.L. performed research; X.M., Y.Z., X.Z., L.L., and J.X. analyzed data; and X.M., Y.Z., E.B., L.L., and J.X. wrote the paper. *X.M. and Y.Z. contributed equally to this work. This work was supported by the National Natural Science Foundation of China (Grant 31661143038 and 31800890), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX05), Shanghai Sailing program (17YF1426800), Shanghai Tongji University Education Development Foundation (to L.L.) and the the Israel Science Foundation (2523/16). We thank Dr. Guoping Feng (Massachusetts Institute of Technology) for generously sharing the ChATChR2-EYFP mouse line. The authors declare no competing financial interests. Correspondence should be addressed to Longnian Lin at or Jiamin Xu at xujiamin@ Copyright © 2020 the authors

Publisher Copyright:
Copyright © 2020 the authors


  • Acetylcholine
  • Hippocampus
  • Medial septum
  • Muscarinic receptors
  • Sharp wave-ripple
  • Optogenetics/methods
  • Muscarinic Antagonists/pharmacology
  • Theta Rhythm/drug effects
  • Action Potentials/drug effects
  • Hippocampus/chemistry
  • Male
  • Mice, Transgenic
  • Cholinergic Neurons/chemistry
  • Cholinergic Agonists/pharmacology
  • Receptor, Muscarinic M2/agonists
  • Animals
  • Receptors, Muscarinic/physiology
  • Mice
  • Receptor, Muscarinic M4/agonists
  • Organ Culture Techniques

ASJC Scopus subject areas

  • Medicine (all)


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