BMAL1 knockout macaque monkeys display reduced sleep and psychiatric disorders
Peiyuan Qiu1,2, Jian Jiang1,3,2, Zhen Liu1,2
1Institute 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.
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.
Insights
Researchers created BMAL1 knockout monkeys using CRISPR/Cas9 to model circadian disruption. These monkeys exhibit sleep issues, hormonal imbalances, and psychiatric symptoms, offering a new primate model for studying and treating circadian and related disorders.
Area of Science:
- Neuroscience
- Genetics
- Chronobiology
Background:
- Circadian disruption is linked to metabolic, psychiatric, and age-related diseases.
- Non-human primate models are crucial for developing therapeutic strategies for these disorders.
Purpose of the Study:
- To generate BMAL1 knockout (KO) cynomolgus monkeys for studying circadian rhythm disorders.
- To investigate the physiological and behavioral consequences of BMAL1 deficiency in a primate model.
Main Methods:
- CRISPR/Cas9 gene editing was used to create BMAL1 KO cynomolgus monkey embryos.
- Behavioral analyses included monitoring locomotion and sleep patterns.
- Physiological assessments involved measuring blood hormone levels and conducting auditory oddball tests.
Main Results:
- BMAL1 KO monkeys displayed increased nocturnal activity and reduced sleep, worsened by constant light.
- Markedly dampened and arrhythmic blood hormone levels indicated physiological circadian disruption.
- These monkeys showed anxiety, depression, elevated cortisol, and sensory processing deficits, mirroring human conditions.
Conclusions:
- BMAL1 KO monkeys serve as a valuable model for circadian rhythm and psychiatric disorder research.
- This primate model can aid in developing novel therapeutic interventions for circadian and related human diseases.
