PMID- 28465238 OWN - NLM STAT- MEDLINE DCOM- 20180319 LR - 20200106 IS - 1873-474X (Electronic) IS - 0736-5748 (Linking) VI - 60 DP - 2017 Aug TI - Repetitive stress leads to impaired cognitive function that is associated with DNA hypomethylation, reduced BDNF and a dysregulated HPA axis. PG - 63-69 LID - S0736-5748(16)30284-2 [pii] LID - 10.1016/j.ijdevneu.2017.04.004 [doi] AB - Exposure to repetitive stress has a negative influence on cognitive-affective functioning, with growing evidence that these effects may be mediated by a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, abnormal neurotrophic factor levels and its subsequent impact on hippocampal function. However, there are few data about the effect of repetitive stressors on epigenetic changes in the hippocampus. In the present study, we examine how repetitive restrain stress (RRS) affects cognitive-affective functioning, HPA axis regulation, brain-derived neurotrophic factor (BDNF) levels, and global hippocampal DNA methylation. RRS was induced in rats by restraining the animals for 6h per day for 28 days. The novel object recognition test (NORT) was used to assess cognitive functioning and the open field test (OFT) was performed to assess anxiety-like behavior during the last week of stress. Hippocampal BDNF levels, glucocorticoid (GR) and mineralocorticoid (MR) receptor mRNA were assessed using real-time PCR and confirmed with Western blot, while ELISAs were used to determine plasma corticosterone levels and the global methylation status of the hippocampus. Animals exposed to repetitive stress demonstrated significant alterations in the NORT and OFT, had significantly increased plasma corticosterone and significantly decreased hippocampal BDNF concentrations. The expression levels of GR and MR mRNA and protein levels of these genes were significantly decreased in the stressed group compared to control animals. The global DNA methylation of the hippocampal genome of stressed animals was also significantly decreased compared to controls. The data here are consistent with previous work emphasizing the role of the HPA axis and neurotrophic factors in mediating cognitive-affective changes after exposure to repetitive stressors. Our findings, however, extend the literature by indicating that epigenetic alterations in the hippocampal genome may also play an important role in the development of hippocampus-associated behavioral abnormalities. CI - Copyright (c) 2017 ISDN. Published by Elsevier Ltd. All rights reserved. FAU - Makhathini, Khayelihle B AU - Makhathini KB AD - Department of Human Physiology, College of Health Sciences, University of KwaZulu- Natal, Durban, South Africa. Electronic address: makhathinik@ukzn.ac.za. FAU - Abboussi, Oualid AU - Abboussi O AD - Department of Human Physiology, College of Health Sciences, University of KwaZulu- Natal, Durban, South Africa. FAU - Stein, Dan J AU - Stein DJ AD - Department of Psychiatry, University of Cape Town, Cape Town, South Africa. FAU - Mabandla, Musa V AU - Mabandla MV AD - Department of Human Physiology, College of Health Sciences, University of KwaZulu- Natal, Durban, South Africa. FAU - Daniels, William M U AU - Daniels WMU AD - School of Physiology, University of the Witwatersrand, Johannesburg, South Africa. LA - eng PT - Journal Article DEP - 20170429 PL - United States TA - Int J Dev Neurosci JT - International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience JID - 8401784 RN - 0 (Brain-Derived Neurotrophic Factor) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cognition Disorders/etiology/*physiopathology MH - DNA Methylation MH - Down-Regulation MH - Hippocampus/*physiopathology MH - Hypothalamo-Hypophyseal System/*physiopathology MH - Male MH - Pituitary-Adrenal System/*physiopathology MH - Rats MH - Rats, Sprague-Dawley MH - Recurrence MH - Stress, Psychological/complications/*physiopathology OTO - NOTNLM OT - Anxiety OT - Cognitive behavior OT - DNA methylation OT - HPA axis OT - Hippocampus OT - Repetitive stress EDAT- 2017/05/04 06:00 MHDA- 2018/03/20 06:00 CRDT- 2017/05/04 06:00 PHST- 2016/10/09 00:00 [received] PHST- 2017/03/13 00:00 [revised] PHST- 2017/04/11 00:00 [accepted] PHST- 2017/05/04 06:00 [pubmed] PHST- 2018/03/20 06:00 [medline] PHST- 2017/05/04 06:00 [entrez] AID - S0736-5748(16)30284-2 [pii] AID - 10.1016/j.ijdevneu.2017.04.004 [doi] PST - ppublish SO - Int J Dev Neurosci. 2017 Aug;60:63-69. doi: 10.1016/j.ijdevneu.2017.04.004. Epub 2017 Apr 29.