BMAL1 knockout macaque monkeys display reduced sleep and psychiatric disorders

Peiyuan Qiu; Jian Jiang; Zhen Liu; Yijun Cai; Tao Huang; Yan Wang; Qiming Liu; Yanhong Nie; Fang Liu; Jiumu Cheng; Qing Li; Yun-Chi Tang; Mu-Ming Poo; Qiang Sun; Hung-Chun Chang

doi:10.1093/nsr/nwz002

BMAL1 knockout macaque monkeys display reduced sleep and psychiatric disorders

Natl Sci Rev. 2019 Jan;6(1):87-100. doi: 10.1093/nsr/nwz002. Epub 2019 Jan 24.

Authors

Peiyuan Qiu^{1

2}, Jian Jiang^{1

3

2}, Zhen Liu^{1

2}, Yijun Cai^{1

2}, Tao Huang⁴, Yan Wang^{1

2}, Qiming Liu^{1

2}, Yanhong Nie^{1

2}, Fang Liu^{1

5

2}, Jiumu Cheng^{1

2}, Qing Li^{1

2}, Yun-Chi Tang⁴, Mu-Ming Poo^{1

2}, Qiang Sun^{1

2}, Hung-Chun Chang^{1

3

2}

Affiliations

¹ Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
² Shanghai Research Center for Brain Science and Brain-inspired Technology, Shanghai 200031, China.
³ Dynamic Brain Signal Analysis Facility, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁵ College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.

Abstract

Circadian disruption is a risk factor for metabolic, psychiatric and age-related disorders, and non-human primate models could help to develop therapeutic treatments. Here, we report the generation of BMAL1 knockout cynomolgus monkeys for circadian-related disorders by CRISPR/Cas9 editing of monkey embryos. These monkeys showed higher nocturnal locomotion and reduced sleep, which was further exacerbated by a constant light regimen. Physiological circadian disruption was reflected by the markedly dampened and arrhythmic blood hormonal levels. Furthermore, BMAL1-deficient monkeys exhibited anxiety and depression, consistent with their stably elevated blood cortisol, and defective sensory processing in auditory oddball tests found in schizophrenia patients. Ablation of BMAL1 up-regulated transcriptional programs toward inflammatory and stress responses, with transcription networks associated with human sleep deprivation, major depressive disorders, and aging. Thus, BMAL1 knockout monkeys are potentially useful for studying the physiological consequences of circadian disturbance, and for developing therapies for circadian and psychiatric disorders.

Keywords: BMAL1; aging; circadian rhythms; macaque monkey; psychosis; sleep disruption.