Dual and plasticity-dependent regulation of cerebello-zona incerta circuits on anxiety-like behaviors

Yue Zhao, Jin-Tao Wu, Jia-Bin Feng, Xin-Yu Cai, Xin-Tai Wang, Luxi Wang, Wei Xie, Yan Gu, Jun Liu (), Wei Chen (), Lin Zhou () and Ying Shen ()
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Yue Zhao: Guangzhou Medical University
Jin-Tao Wu: Hangzhou Normal University
Jia-Bin Feng: Zhejiang University School of Medicine
Xin-Yu Cai: Zhejiang University School of Medicine
Xin-Tai Wang: Hangzhou Normal University
Luxi Wang: Zhejiang University School of Medicine
Wei Xie: Southeast University
Yan Gu: Zhejiang University School of Medicine
Jun Liu: Guangzhou Medical University
Wei Chen: Zhejiang University School of Medicine
Lin Zhou: Zhejiang University School of Medicine
Ying Shen: Guangzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Clinical observation has identified cerebellar cognitive affective syndrome, which is characterized by various non-motor dysfunctions such as social disorders and anxiety. Increasing evidence has revealed reciprocal mono-/poly-synaptic connections of cerebello-cerebral circuits, forming the concept of the cerebellar connectome. In this study, we demonstrate that neurons in the cerebellar nuclei (CN) of male mice project to a subset of zona incerta (ZI) neurons through long-range glutamatergic and GABAergic transmissions, both capable of encoding acute stress. Furthermore, activating or inhibiting glutamatergic and GABAergic transmissions in the CN → ZI pathway can positively or negatively regulate anxiety and place preference through presynaptic plasticity-dependent mechanisms, as well as mediate motor-induced alleviation of anxiety. Our data support the close relationship between the cerebellum and emotional processes and suggest that targeting cerebellar outputs may be an effective approach for treating anxiety.

Date: 2025
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DOI: 10.1038/s41467-025-58727-0

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