Time-restricted feeding entrains long-term behavioral changes through the IGF2-KCC2 pathway

Qiaocheng Zhai; Yizhun Zeng; Yue Gu; Zhihao Li; Tao Zhang; Baoshi Yuan; Tao Wang; Jie Yan; Han Qin; Ling Yang; Xiaowei Chen; Antonio Vidal-Puig; Ying Xu

doi:10.1016/j.isci.2022.104267

Time-restricted feeding entrains long-term behavioral changes through the IGF2-KCC2 pathway

iScience. 2022 Apr 18;25(5):104267. doi: 10.1016/j.isci.2022.104267. eCollection 2022 May 20.

Authors

Qiaocheng Zhai¹, Yizhun Zeng¹, Yue Gu¹, Zhihao Li¹, Tao Zhang¹, Baoshi Yuan¹, Tao Wang¹, Jie Yan², Han Qin³, Ling Yang², Xiaowei Chen³, Antonio Vidal-Puig^{4

5}, Ying Xu¹

Affiliations

¹ Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Medical School of Soochow University, Suzhou, Jiangsu 215123, China.
² School of Mathematical Sciences, Soochow University, Suzhou 215006, P. R. China.
³ Brain Research Center and State Key Laboratory of Trauma, Burns, and Combined Injury, Third Military Medical University, Chongqing 400038, China.
⁴ University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, UK.
⁵ Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei Area, Nanjing, P.R. of China.

Abstract

The suprachiasmatic nucleus (SCN) integrates light and systemic signals from peripheral tissues to coordinate physiology and behavior daily rhythms. However, the contribution that nutrients and feeding patterns provide to the SCN network regulation remains controversial. Here, we found that time-restricted feeding (TRF) in ZT0-4 (Zeitgeber Time) generates a robust and long-term shift in locomotor behavior and increased wakefulness. Intracellular Ca²⁺ signals in SCN GABAergic neurons of freely moving mice showed significant activation after ZT0-4 TRF treatment. Furthermore, RNA-seq profiling of SCN showed that TRF during ZT0-4 increased Insulin-like Growth Factor 2 (Igf2) expression and dysregulated ion transporters, including the downregulation of Kcc2. SCN neuron-specific loss of function of Kcc2 amplified ZT0-4 TRF induced aftereffect. Moreover, overexpression of IGF2 in SCN GABAergic neurons extended the locomotion range, mirroring the TRF aftereffect. In summary, our study showed that the IGF2-KCC2 pathway plays an important role for TRF induced behavior changes.

Keywords: Behavioral neuroscience; Molecular neuroscience; Neuroscience.

Abstract

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