PMID- 37390967 OWN - NLM STAT- MEDLINE DCOM- 20230814 LR - 20230814 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 452 DP - 2023 Aug 24 TI - PI3K-AKT-mTOR signaling pathway regulates autophagy of hippocampal neurons in diabetic rats with chronic unpredictable mild stress. PG - 114558 LID - S0166-4328(23)00276-0 [pii] LID - 10.1016/j.bbr.2023.114558 [doi] AB - It is reported that the co-morbidities of diabetes and depression will be a new challenge for humanity. However, the underlying mechanism is not clear. The present study investigated the histopathology, autophagy of hippocampal neurons, and the PI3K-AKT- mTOR signaling pathway in type 2 diabetes with depression（T2DD） rats. The results showed that, the chronic unpredictable mild stress (CUMS), Type 2 diabetes mellitus (T2DM) and T2DD in rats were induced successfully. Compared with the CUMS and T2DM groups, the T2DD group performed significantly fewer autonomic activities in the open-field test, and longer immobile in the force swimming test, and increasing of Corticosterone (CORT) in blood. The number of pyknotic neurons at cornu ammonis 1 (CA1) and dentate gyrus (DG) of the hippocampus in T2DD was significantly increased compared with CUMS and T2DM groups. Moreover, compared with the CUMS and T2DM groups, the mitochondrial autophagosomes were most abundant in the T2DD group. As shown in western blot and immunofluorescence, compared with the control group, in the CUMS, T2DM and T2DD groups, significantly increased expression of Beclin-1 and LC3B and decreased P62 were detected. In the PC12 cells, the relative amount of parkin and LC3B in the CORT+HG group was significantly higher than that in the CORT and HG groups. Compared with the control group, p-AKT/AKT and p-mTOR/mTOR in CUMS, T2DM and T2DD groups were significantly decreased. Compared with the CUMS group, p-AKT/AKT, p-PI3K/PI3K and p-mTOR/mTOR in the T2DD group exhibited further decrease. Similar results were obtained in PC12 cells in vitro. It is suggests that memory and cognitive impairment in rats with co-morbidities of diabetes and depression might be related with hippocampal neuronal damage and autophagy increase, which was involved in the PI3K-AKT-mTOR signaling pathway. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Xu, Jie AU - Xu J AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China; Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Key Laboratory of Reproduction and Genetics, Ningxia Medical University, Yinchuan, Ningxia 750004, China. FAU - Zheng, Bowen AU - Zheng B AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. FAU - Ma, Yanmei AU - Ma Y AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. FAU - Zhang, Xiaopeng AU - Zhang X AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. FAU - Cheng, Jianhua AU - Cheng J AD - Department of Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan, Ningxia 750004, China. FAU - Yang, Jing AU - Yang J AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. FAU - Li, Peng AU - Li P AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. FAU - Zhang, Jianzhong AU - Zhang J AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. Electronic address: zhangjz@nxmu.edu.cn. FAU - Jing, Li AU - Jing L AD - Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, China. Electronic address: 1203220205@qq.com. FAU - Xu, Fang AU - Xu F AD - Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Key Laboratory of Reproduction and Genetics, Ningxia Medical University, Yinchuan, Ningxia 750004, China. Electronic address: xufang@nxmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230628 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.1.1 (mTOR protein, rat) SB - IM MH - Rats MH - Animals MH - Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - *Diabetes Mellitus, Experimental/metabolism MH - Signal Transduction/physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Hippocampus/metabolism MH - Autophagy/physiology MH - Neurons/metabolism OTO - NOTNLM OT - Autophagy OT - Chronic unpredictable mild stress OT - Hippocampal OT - PI3K-AKT- mTOR signaling pathway OT - Type 2 diabetic model rats COIS- Conflict of interest The authors declare no competing interests. EDAT- 2023/07/01 11:41 MHDA- 2023/08/14 06:42 CRDT- 2023/06/30 19:14 PHST- 2023/04/12 00:00 [received] PHST- 2023/06/05 00:00 [revised] PHST- 2023/06/26 00:00 [accepted] PHST- 2023/08/14 06:42 [medline] PHST- 2023/07/01 11:41 [pubmed] PHST- 2023/06/30 19:14 [entrez] AID - S0166-4328(23)00276-0 [pii] AID - 10.1016/j.bbr.2023.114558 [doi] PST - ppublish SO - Behav Brain Res. 2023 Aug 24;452:114558. doi: 10.1016/j.bbr.2023.114558. Epub 2023 Jun 28.