School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China.
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Behav Brain Res. 2020 Oct 1;395:112838. doi: 10.1016/j.bbr.2020.112838. Epub 2020 Aug 1.
The prefrontal cortex (PFC) plays an important role in regulating anxiety-like phenotypes and social behaviors, and impairments in this brain region has been linked to social deficits in mammals. Childhood obesity is associated with an increased risk of neuropsychiatric behavioral abnormalities, including attenuated social preference and increased anxiety-like behaviors in adulthood. However, little data are available on the impact of obesity during adolescence on PFC-dependent behaviors. Herein, we use the mice pups to illuminate whether and how high-fat diet (HFD) feeding in adolescence affects medial prefrontal cortex (mPFC)-dependent behaviors, and what the underlying cellular and molecular mechanism is. We found that juvenile HFD feeding results in the accumulation of senescent astrocytes and microglia in the mPFC of mice. Furthermore, we found a causal link between the accumulation of senescent glial cells and HFD-induced neuropsychiatric behavioral abnormalities. Pharmacological clearance of senescent glial cells in HFD-fed mice enhances neuronal activity and reserves synaptic excitatory/inhibitory balance, thus preserving normal behaviors. Collectively, these results show that senescent glial cells play a significant role in the initiation and progression of juvenile obesity-mediated neuropsychiatric behavioral abnormalities, and suggest that targeting senescent glial cells may provide a therapeutic avenue for the treatment of obesity-related neuropsychiatric disorders in children.
前额皮质（prefrontal cortex，PFC）在调节焦虑样表型和社交行为方面发挥着重要作用，该脑区的损伤与哺乳动物的社交缺陷有关。儿童肥胖与神经精神行为异常的风险增加有关，包括成年后社交偏好减弱和焦虑样行为增加。然而，关于青春期肥胖对 PFC 依赖行为的影响的数据很少。在此，我们使用幼鼠来阐明青春期高脂肪饮食（high-fat diet，HFD）喂养是否以及如何影响内侧前额叶皮层（medial prefrontal cortex，mPFC）依赖行为，以及潜在的细胞和分子机制是什么。我们发现，幼鼠 HFD 喂养会导致 mPFC 中衰老星形胶质细胞和小胶质细胞的积累。此外，我们发现衰老胶质细胞的积累与 HFD 诱导的神经精神行为异常之间存在因果关系。在 HFD 喂养的小鼠中清除衰老的胶质细胞可增强神经元活性并维持突触兴奋性/抑制性平衡，从而维持正常行为。综上所述，这些结果表明衰老的胶质细胞在启动和进展青少年肥胖介导的神经精神行为异常中起重要作用，并提示靶向衰老的胶质细胞可能为治疗儿童肥胖相关神经精神障碍提供一种治疗途径。
