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The dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer’s disease

Molecular Psychiatry (2026)Cite this article

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Abstract

Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer’s disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.

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Fig. 1: Brian regions showing differences of PCx connectivity between MCI and HC.
Fig. 2: AD mice exhibits olfactory memory retrieval impairment and PCx engram cell dysfunction.
Fig. 3: PCx-IL engram neurons circuit mediate AD olfactory memory impairment.
Fig. 4: Optogenetic stimulation of PCx olfactory memory engram neurons induces IL engram neuronal activation in WT and AD mice.
Fig. 5: Single-cell transcriptomics resolves the olfactory memory associated different genes in the WT and AD mice.
Fig. 6: Dynamics of engram connectivity correlate with olfactory memory impairment in AD.
Fig. 7: HFS promotes the retrieval of olfactory memory in AD mice.
Fig. 8

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Acknowledgements

We thank the Biological and Medical Engineering Core Facilities of Beijing Institute of Technology for supplying our experimental equipment. MRI data were provided by OASIS-3: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352.

Funding

This work was supported by Shenzhen Municipal Key Project for Basic Research (Grant No. JCYJ20241202130511015), Shenzhen Natural Science Foundation General Project (Grant No. JCYJ20230807142704008), Open Project of the State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology (Grant No. SKLBI-K2025002), Guangdong Province General Higher Education Institution Innovative Research Team Project (Natural Sciences) (Grant No. 2024KCXTD016) and.National Natural Science Foundation of China (Grant No. 82371446, 32371030, 32571170, 82501439), Natural Science Foundation of Hebei Province, H2024206232, Technology Research Program of Hebei Provincial Health Commission Grant No. ZF2024142. the Ministry of Science and Technology of China (STI2030-Major Projects 2022ZD0206800), the Scientific Project of Beijing Life Science Academy (2023000CB0010), the scientific research program of innovation platform in State Tobacco Monopoly Administration.

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Author notes

  1. These authors contributed equally: Yan Yan, Da Song, Guangfei Li.

Authors and Affiliations

  1. International University Park Road, Dayun New Town, Longgang District, Shenzhen MSU-BIT University, Shenzhen, China

    Yan Yan, Hui Li & Qing Hong

  2. Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Children and Adolescents’ Health and Diseases, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Yan Yan, Junjie Li, Yayan Pang & Zhifang Dong

  3. Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China

    Yan Yan, Xiaoyun Liu, Ding Yu & Fangfang Ma

  4. Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China

    Da Song, Yuanhong Tang, Danyang Li, Yue Jin, Yujun Deng, Yunjie Qiu, Zhenzhen Quan & Junjun Ni

  5. Department of Biomedical Engineering, College of Chemistry and Life Science, Beijing University of Technology, Beijing, China

    Guangfei Li

  6. Flavour Science Laboratory, Beijing Life Science Academy (BLSA), Beijing, 102209, China

    Jian Mao

  7. Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China

    Yong Cheng

  8. Advanced Innovation Center for Human Brain Protection, Capital Medical University; The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China

    Zhe Wang

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Contributions

Y Yan, DS, GFL, ZFD and HQ conceived and designed the studies and wrote the papers. Y Yan, YHT, YJ and YJD. performed optogenetics and behavioral tests. DYL, YJQ, carried out fibre photometry recordings and immunohistochemistry and cell counting. Y Yan, JJie L, YYan P, performed electrophysiology. DS, GL, XY L analyzed the data and revised papers. JM, ZW, HL and YC performed imaging and revised papers. All authors contributed to the data analysis and presentation in the paper.

Corresponding authors

Correspondence to Zhifang Dong or Qing Hong.

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The authors declare no competing interests.

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Committee on animal Research. The research consent to institutional ethical regulations: Biological and Medical Ethics Committee, Minzu University of China. Ethical approval for the OASIS-3 dataset was obtained from the Institutional Review Board of Washington University, and all participants provided written informed consent.

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Yan, Y., Song, D., Li, G. et al. The dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer’s disease. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03550-2

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