Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy
ObjectivesTo explore the relationship between leucine in cerebrospinal fluid (CSF) and cognitive dysfunction in rats with early life stress (ELS) induced mental illness, and pathophysiological mechanism involved.MethodsThe maternal separation (MS), an animal paradigm used widely as a preclinical mod...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.1060712/full |
| _version_ | 1797961518335131648 |
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| author | Xiaotian Wang Xue Wang Fang Xie Zhaowei Sun Bomin Guo Feng Li Shida Wang Ying Wang Yingrui Tian Yun Zhao Lingjia Qian |
| author_facet | Xiaotian Wang Xue Wang Fang Xie Zhaowei Sun Bomin Guo Feng Li Shida Wang Ying Wang Yingrui Tian Yun Zhao Lingjia Qian |
| author_sort | Xiaotian Wang |
| collection | DOAJ |
| description | ObjectivesTo explore the relationship between leucine in cerebrospinal fluid (CSF) and cognitive dysfunction in rats with early life stress (ELS) induced mental illness, and pathophysiological mechanism involved.MethodsThe maternal separation (MS), an animal paradigm used widely as a preclinical model of ELS which is one of the important risk factors for mental disorders. Behavioral experiments including open-field test, sucrose preference, object recognition and Morris water maze tests, Nissl staining, transmission electron microscopy and WES were employed in the present study.ResultsThe behavioral results showed that MS rats were more prone to cognitive impairment and depression-and-anxiety-like behaviors than controls, including spatial self-exploration ability, memory ability, and spatial learning and memory function. Nissl staining analysis indicated that the number of neurons in the CA1 and CA3 regions of the hippocampus significantly decreased and the arrangement of nerve cells was abnormal. The leucine levels were decreased in the CSF of MS rats and highly correlated with the number of hippocampal neurons, and yet leucine supplementation improved the degree of MS-induced cognitive impairment. Furthermore, there were autophagosomes in the hippocampus of the low-leucine diet rats of the control and MS group but not in the high-leucine diet MS group by transmission electron microscopy. The protein expression of Beclin-1 in the hippocampus was significantly increased in the MS normal diet group and MS low-leucine diet group, yet decreased in the MS high-leucine diet group compared with the MS low-leucine diet group. Meanwhile, the Bcl-2/Bax ratio was significantly decreased in the control low-leucine diet group, MS normal diet group and MS low-leucine diet group. Ultimately, in vitro experiments suggested that leucine deficiency could activate neuronal autophagy including enhanced LC3II/LC3I and mRFP-GFP-LC3, which was consistent with the in vivo results, and the cell apoptosis rate and lactate dehydrogenase (LDH) cytotoxicity were also increased with leucine deficiency, while the above effects could be partly reversed by autophagy inhibitor treatment.ConclusionsMS model caused adult male rats to be susceptible to cognitive dysfunction, which may regulate autophagy in hippocampal neurons through leucine metabolism in CSF. |
| first_indexed | 2024-04-11T00:59:22Z |
| format | Article |
| id | doaj.art-01e48de299a549399fe83067255b2746 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-11T00:59:22Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-01e48de299a549399fe83067255b27462023-01-04T17:46:03ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-01-011610.3389/fncel.2022.10607121060712Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagyXiaotian WangXue WangFang XieZhaowei SunBomin GuoFeng LiShida WangYing WangYingrui TianYun ZhaoLingjia QianObjectivesTo explore the relationship between leucine in cerebrospinal fluid (CSF) and cognitive dysfunction in rats with early life stress (ELS) induced mental illness, and pathophysiological mechanism involved.MethodsThe maternal separation (MS), an animal paradigm used widely as a preclinical model of ELS which is one of the important risk factors for mental disorders. Behavioral experiments including open-field test, sucrose preference, object recognition and Morris water maze tests, Nissl staining, transmission electron microscopy and WES were employed in the present study.ResultsThe behavioral results showed that MS rats were more prone to cognitive impairment and depression-and-anxiety-like behaviors than controls, including spatial self-exploration ability, memory ability, and spatial learning and memory function. Nissl staining analysis indicated that the number of neurons in the CA1 and CA3 regions of the hippocampus significantly decreased and the arrangement of nerve cells was abnormal. The leucine levels were decreased in the CSF of MS rats and highly correlated with the number of hippocampal neurons, and yet leucine supplementation improved the degree of MS-induced cognitive impairment. Furthermore, there were autophagosomes in the hippocampus of the low-leucine diet rats of the control and MS group but not in the high-leucine diet MS group by transmission electron microscopy. The protein expression of Beclin-1 in the hippocampus was significantly increased in the MS normal diet group and MS low-leucine diet group, yet decreased in the MS high-leucine diet group compared with the MS low-leucine diet group. Meanwhile, the Bcl-2/Bax ratio was significantly decreased in the control low-leucine diet group, MS normal diet group and MS low-leucine diet group. Ultimately, in vitro experiments suggested that leucine deficiency could activate neuronal autophagy including enhanced LC3II/LC3I and mRFP-GFP-LC3, which was consistent with the in vivo results, and the cell apoptosis rate and lactate dehydrogenase (LDH) cytotoxicity were also increased with leucine deficiency, while the above effects could be partly reversed by autophagy inhibitor treatment.ConclusionsMS model caused adult male rats to be susceptible to cognitive dysfunction, which may regulate autophagy in hippocampal neurons through leucine metabolism in CSF.https://www.frontiersin.org/articles/10.3389/fncel.2022.1060712/fullmaternal separation stresscognitive impairmentleucinecerebrospinal fluidautophagymental disorders |
| spellingShingle | Xiaotian Wang Xue Wang Fang Xie Zhaowei Sun Bomin Guo Feng Li Shida Wang Ying Wang Yingrui Tian Yun Zhao Lingjia Qian Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy Frontiers in Cellular Neuroscience maternal separation stress cognitive impairment leucine cerebrospinal fluid autophagy mental disorders |
| title | Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy |
| title_full | Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy |
| title_fullStr | Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy |
| title_full_unstemmed | Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy |
| title_short | Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy |
| title_sort | leucine mediates cognitive dysfunction in early life stress induced mental disorders by activating autophagy |
| topic | maternal separation stress cognitive impairment leucine cerebrospinal fluid autophagy mental disorders |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.1060712/full |
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