2. Academic Validation
  3. BDNF and NLRP3 signaling differentially regulate formation and retrieval of nitrous oxide (N2O)-related rewarding memory in dorsal hippocampus CA3 region

BDNF and NLRP3 signaling differentially regulate formation and retrieval of nitrous oxide (N2O)-related rewarding memory in dorsal hippocampus CA3 region

  • Int Immunopharmacol. 2026 Mar 15:173:116327. doi: 10.1016/j.intimp.2026.116327.
Huarong Shen 1,  Yatong Shi 1,  Jiancheng Xu 1,  Yuxu Ren 1,  Xiaoyu Xia 1,  Tianyi Zang 1,  Yi-Feng Cheng 2,  Junlong Zhang 3,  Tengfei Ma 4,  Fangyuan Yin 5
Affiliations

Affiliations

  • 1 Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular &Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
  • 2 School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
  • 3 Department of Anesthesiology, Jinshan Hospital of Fudan University, Shanghai 201508, China. Electronic address: [email protected].
  • 4 Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular &Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China; Department of Toxicology, the Key laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Province Innovation center for Brain-Inspired intelligence technology, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 5 Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular &Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China; College of Forensic Science, School of Medicine, Xi'an Jiaotong University, Xi'an, China.; Jiangsu Province Innovation center for Brain-Inspired intelligence technology, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 41662814 DOI: 10.1016/j.intimp.2026.116327
Abstract

The formation and retrieval of reward memories within the hippocampus are critical mechanisms underlying the development of substance use disorder. Nitrous oxide (N2O), an inhalant with significant abuse potential, is believed to hijack these processes, yet the precise hippocampal mechanisms remain unknown. Here, we reported that N2O-related memory stages are differentially regulated by BDNF and NLRP3 signaling in the dorsal hippocampus CA3 region. First, we found that N2O exposure induces conditioned place preference (CPP) and preferentially increases the activity of hippocampal CA3 neurons. Furthermore, N2O concurrently enhances both the BDNF expression and the microglia activity in hippocampal CA3 region. The mechanisms are involved in activation of both BDNF-TrkB-pAKT and the microglia-NLRP3 signaling pathways. Interestingly, knockdown of BDNF expression in the CA3 region reduces retrieval, but not formation stage, of CPP behavior. Whole-cell patch-clamp recordings further demonstrated that CA3-specific BDNF knockdown abolishes the N2O-induced potentiation of glutamatergic transmission. Finally, both pharmacological microglial inhibition and germline NLRP3 deletion prevented the N2O-induced formation stage of CPP behavior. Our study elucidates a novel, stage-specific regulatory mechanism in which BDNF-TrkB-pAKT and the microglia-NLRP3 signaling within the hippocampal CA3 differentially governs the retrieval versus formation of N2O reward memory, revealing distinct targets for therapeutic intervention.

Keywords

Brain-derived neurotrophic factor (BDNF); Conditioned place preference (CPP); Hippocampus CA3; Memory; Nitrous Oxide.

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