2. Academic Validation
  3. Molecular brake on firing pattern transitions in MHbChAT neurons to mediate nicotine-withdrawal-induced anxiety

Molecular brake on firing pattern transitions in MHbChAT neurons to mediate nicotine-withdrawal-induced anxiety

  • Neuron. 2026 Mar 27:S0896-6273(26)00126-1. doi: 10.1016/j.neuron.2026.02.020.
Zhi-Wei Zheng 1,  Peng-Xiang Min 1,  Yi-Ling Luo 1,  Xing-Feng Mao 1,  Yi-Xuan Zhang 2,  Xiu-Xiu Liu 2,  Ming Lu 3,  Eugene Yujun Xu 4,  Feng Han 5,  Ying-Mei Lu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Modern Toxicology of the Ministry of Education, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 2 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 3 Jiangsu Key Laboratory of Neurodegeneration, Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China.
  • 4 Cellular Screening Center, The University of Chicago, 900 E. 57th Street, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 5 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Jiangsu Province Innovation Center for Brain-Inspired Intelligence Technology, Nanjing 210029, China. Electronic address: [email protected].
  • 6 Key Laboratory of Modern Toxicology of the Ministry of Education, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; Jiangsu Province Innovation Center for Brain-Inspired Intelligence Technology, Nanjing 210029, China; Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: [email protected].
PMID: 41903536 DOI: 10.1016/j.neuron.2026.02.020
Abstract

Cholinergic neurons exhibit distinct firing patterns underlying diverse physiological and pathological states, but the mechanisms governing their dynamic switching, particularly in negative emotional contexts, remain unclear. Here, we demonstrate that medial habenula cholinergic (MHbChAT) neurons transition from tonic to burst firing during nicotine withdrawal, driving anxiety-like behaviors in mice. Integrating transcriptomics, electrophysiology, and genetic manipulation, we identified the RNA-binding protein pumilio 1 (Pum1) as a critical brake on this switch. Pum1 binds Cacna1g mRNA (encoding Cav3.1) at nucleotides 6,498-6,501, promoting its decay. MHbChAT neurons comprise two subpopulations: burst-firing Pum1- and tonic-firing Pum1+ neurons. Withdrawal downregulates Pum1, derepressing Cav3.1 to induce pathological bursting. Genetic or pharmacological suppression of Cav3.1, or Pum1 overexpression, rescues burst firing and anxiety-like behaviors. Our study unveils MHbChAT neurons' burst firing as a causal driver of anxiety and reveals the Pum1-Cav3.1 axis as a master regulator of firing plasticity, offering a potential targeted therapeutic strategy for cholinergic dysfunction-related disorders.

Keywords

Cav3.1; burst-firing transition; cholinergic neurons; medial habenula; nicotine withdrawal anxiety; pumilio 1.

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