Sumitomo Akiko, Ueta Keisho, Mauchi Sayaka, Hirai Kazuko, Horike Kouta, Hikida Takatoshi, Sakurai Takeshi, Sawa Akira, Tomoda Toshifumi
Kyoto University Graduate School of Medicine, Medical Innovation Center, Kyoto, Japan.
Johns Hopkins University School of Medicine, Dept. of Psychiatry, Baltimore, MD, USA.
Neurosci Res. 2017 Apr;117:54-61. doi: 10.1016/j.neures.2016.12.004. Epub 2016 Dec 23.
Alcoholism is a psychiatric condition that develops through neuroadaptations in response to neuronal stresses caused by chronic ethanol intake. Neurons can adapt to ethanol-induced metabolic changes by activating cellular protective mechanisms, including autophagy. Here we show that expression of Ulk1, a gene critical to the regulation of autophagy, was affected in the prefrontal cortex (PFC) of mice following chronic intermittent ethanol (CIE) exposure. Consequently, overall levels of Ulk1 activity in the PFC were downregulated, leading to accumulation of p62, a protein that serves as a target for autophagic degradation. In addition, Ulk1-null mice demonstrated decline in the exploratory activity, deficits in the ability to recognize novel objects following CIE exposure, and reduced rate of voluntary ethanol drinking. The data suggest the neuroprotective role for Ulk1-mediated autophagy in the suppression of neuropsychiatric manifestation during ethanol exposure.
酒精中毒是一种精神疾病，它通过神经适应过程发展而来，这种适应是对慢性乙醇摄入所引起的神经元应激的反应。神经元可以通过激活包括自噬在内的细胞保护机制，来适应乙醇诱导的代谢变化。在此我们表明，自噬调节关键基因Ulk1的表达，在慢性间歇性乙醇（CIE）暴露后的小鼠前额叶皮质（PFC）中受到影响。因此，PFC中Ulk1的总体活性水平下调，导致p62积累，p62是一种作为自噬降解靶点的蛋白质。此外，Ulk1基因敲除小鼠在CIE暴露后表现出探索活动下降、识别新物体能力缺陷以及自愿饮酒率降低。这些数据表明Ulk1介导的自噬在乙醇暴露期间对神经精神症状的抑制中具有神经保护作用。
