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Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
Xiao-Lan Wang1,2,3, Sander Kooijman4, Yuanqing Gao2,3
1Université de Strasbourg, Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Strasbourg, France.
Abstract:
Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.
Insights
Disrupting the microglial clock gene Bmal1 enhances brain cell cleanup and protects against obesity and memory loss. This suggests targeting microglial Bmal1 could treat metabolic and cognitive disorders.
Area of Science:
- Neuroscience
- Chronobiology
- Metabolic research
Background:
- Microglia, the brain's immune cells, exhibit circadian rhythms influencing neural function.
- The precise role of this intrinsic clock in microglial function under stimulated conditions, like metabolic stress or memory formation, remains unclear.
Purpose of the Study:
- To investigate the impact of microglial-specific knockdown of the core clock gene Bmal1 on microglial phagocytosis and its functional consequences.
- To determine if Bmal1 regulates microglial responses during metabolic challenges and cognitive processes.
Main Methods:
- Microglia-specific knockdown of the Bmal1 gene in mice.
- High-fat diet (HFD) induction to simulate metabolic stress.
- Assessment of microglial phagocytosis, pro-opiomelanocortin (POMC) retention in the hypothalamus, and hippocampal spine maturation.
- Evaluation of HFD-induced obesity and performance in memory tests.
Main Results:
- Microglia-specific Bmal1 knockdown increased microglial phagocytosis under HFD and during cognitive tasks.
- Enhanced phagocytosis correlated with retained POMC-immunoreactivity and hippocampal spine maturation.
- Loss of Bmal1 protected mice from HFD-induced obesity and improved memory test performance.
Conclusions:
- The intrinsic clock machinery in microglia, regulated by Bmal1, normally restrains phagocytosis.
- Loss of Bmal1 enhances microglial phagocytosis, providing neuroprotection during metabolic stress and learning.
- Microglial Bmal1 is a potential therapeutic target for metabolic and cognitive disorders, including psychiatric diseases.
