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Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala

Molecular Psychiatry volume 27, pages 4050–4063 (2022)Cite this article

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Abstract

Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.

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Fig. 1: Impaired behavioral flexibility is correlated with reduced neuronal activity in the BLA of SAMP8 mice at 5-month.
Fig. 2: Impaired behavioral flexibility is due to the increased necroptosis in the BLA of aged mice.
Fig. 3: The reduction of GSK-3α in the BLA led to the activation of necroptosis and impaired behavioral flexibility of aged mice.
Fig. 4: Restoration of GSK-3α alleviated necroptosis in the BLA and the impairment of behavioral flexibility, and the mTORC1 signaling played an important role in the necroptosis induced by loss of GSK-3α.
Fig. 5: Social isolation accelerated the necroptosis in the BLA and the dysfunction of behavioral flexibility in 4-month-SAMP8 mice.

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Acknowledgements

We thank Dr. James Woodgett for gifting us the GSK-3α-floxed mice. We thank Dr. Yun -Yun Han at Dept. Neurobiology of HUST and Dr. Keqiang Ye at Shenzhen Institutes of Advanced Technology for their constructive comments. We thank Dr. Xiao-Jiang Li and Shi-Hua Li at Jinan University for their generous help on monkey experiments. We thank all the technicians and core facility in the Analytical and Testing Center, Huazhong University of Science and Technology. This study is supported by the Major Project of “Brain Science and Brain-inspired Research” (2022ZD0211800), and National Natural Science Foundation of China (82030032, 32070960, 81871108, 31721002, 81829002), Top-Notch Young Talents Program of China of 2014 to Dr. Ling-Qiang Zhu.

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  1. These authors contributed equally: Juan Zhang, Dan Liu, Peng Fu

Authors and Affiliations

  1. Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Juan Zhang, Zhi-Qiang Liu, Chuan Lai, Chun-Qing Yang, Kai Chen, Wen-Dai Bao, Fan Hu, Youming Lu & Ling-Qiang Zhu

  2. Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Dan Liu

  3. Department of Neurosurgery, Union Hospital, Huazhong University of Science and Technology, Jiefang Avenue No. 1277, 430022, Wuhan, China

    Peng Fu

  4. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hui-Yun Du

  5. Guangdong Key Laboratory of Non-human Primate Research, Guangdong Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China

    Weili Yang

  6. Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan, Hubei, 430071, China

    Jie Wang

  7. Department of Biology, Boston University, Boston, MA, 02215, USA

    Heng-Ye Man

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Contributions

LQZ and DL initiated and designed the study, DL, PF, YML, and HYM supervised the study; JZ performed the molecular biological experiments and animal experiments; CL performed the electrophysiology experiments; JZ, ZQL, and CQY performed animal experiments; WLY provided the monkey brains. DL, LQZ, PF, HYD, JW, WDB, HYM, YL, and KC provide experimental guide; JZ, WDB, FH and LQZ analyzed the data; LQZ and JZ wrote the manuscript.

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Correspondence to Ling-Qiang Zhu.

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Zhang, J., Liu, D., Fu, P. et al. Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala. Mol Psychiatry 27, 4050–4063 (2022). https://doi.org/10.1038/s41380-022-01694-5

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