PMID- 31174163 OWN - NLM STAT- MEDLINE DCOM- 20200518 LR - 20200518 IS - 1873-3360 (Electronic) IS - 0306-4530 (Linking) VI - 107 DP - 2019 Sep TI - Multiple prenatal stresses increase sexual dimorphism in adult offspring behavior. PG - 251-260 LID - S0306-4530(18)30730-3 [pii] LID - 10.1016/j.psyneuen.2019.05.003 [doi] AB - INTRODUCTION: Maternal gestational stress and immune activation have independently been associated with affective and neurodevelopmental disorders across the lifespan. We investigated whether rats exposed to prenatal maternal stressors (PNMS) consisting of psychological stress, interleukin (IL)-1beta or both (two-hit stress) during critical developmental windows displayed a behavioral phenotype representative of these conditions. METHODS: Long-Evans dams were exposed to psychological stressors consisting of restraint stress and forced swimming from gestational day (GD)12 to 18 or to no stress (controls). From GD17 until day of delivery, these same animals were injected with saline or IL-1beta as a second hit and immune stressor (5 mug/day, intraperitoneally). The behavior of F1 offspring adults was tested on the open field test, elevated plus maze and affective exploration task on postnatal days (P)90, 100 and 110 respectively. RESULTS: The effects of PNMS differed depending on the specific testing environment and potentially the age at assessment, especially in female offspring. Both locomotion and anxiety-like behavioral measures were susceptible to PNMS effects. In females, psychological stress increased anxiety-like behavior, whereas IL-1beta had an opposite effect, inducing exploration and risk-taking behavior on the open field test and the elevated plus maze. When present, interactions between both stressors limited the anxiogenic effect of psychological stress on its own. In contrast, prenatal psychological stress increased anxiety-like behavior in adult males overall. A similar anxiogenic effect of IL-1beta was only found on the open field test while the Stress*IL-1beta interaction appeared to limit the effect of either alone. Contrarily, the PNMS effects on anxiety-like behavior on the affective exploration task were highly similar between both sexes. Analysis of males and females together revealed an additive effect of Stress and IL-1beta on the number of exits from the refuge, a measure of risk assessment and thus correlated with anxiety. CONCLUSION: PNMS affected offspring adult behavior in a sex-dependent manner. Effects on females were more variable, whereas psychological stress mostly induced anxiety-like behavior in males. These data highlight the sexual dimorphism in vulnerability to prenatal stressors. Maternal or stress-induced programming of the stress response and neuroinflammation may play an important role in mediating stress effects on offspring adult behavior. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Verstraeten, Barbara S E AU - Verstraeten BSE AD - Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, 227 HMRC, Edmonton, AB T6G 2S2, Canada; Department of Human Structure and Repair, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: barbara.verstraeten@ualberta.ca. FAU - McCreary, J Keiko AU - McCreary JK AD - Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada. FAU - Falkenberg, Erin A AU - Falkenberg EA AD - Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada. FAU - Fang, Xin AU - Fang X AD - Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, 227 HMRC, Edmonton, AB T6G 2S2, Canada. FAU - Weyers, Steven AU - Weyers S AD - Department of Human Structure and Repair, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: steven.weyers@ugent.be. FAU - Metz, Gerlinde A S AU - Metz GAS AD - Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada. Electronic address: gerlinde.metz@uleth.ca. FAU - Olson, David M AU - Olson DM AD - Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, 227 HMRC, Edmonton, AB T6G 2S2, Canada. Electronic address: david.olson@ualberta.ca. LA - eng GR - 363195/CIHR/Canada GR - 119513/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190509 PL - England TA - Psychoneuroendocrinology JT - Psychoneuroendocrinology JID - 7612148 RN - 0 (Interleukin-1beta) SB - IM MH - Animals MH - Anxiety/etiology/physiopathology MH - Behavior, Animal/physiology MH - Brain/drug effects/metabolism MH - Exploratory Behavior/physiology MH - Female MH - Hippocampus/drug effects MH - Interleukin-1beta/metabolism/pharmacology MH - Male MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*physiopathology/psychology MH - Rats MH - Rats, Long-Evans MH - *Sex Characteristics MH - Sex Factors MH - Stress Disorders, Traumatic/etiology/physiopathology MH - Stress, Psychological/complications/*physiopathology OTO - NOTNLM OT - Behavior OT - Brain development OT - Inflammation OT - Prenatal stress OT - Sex differences EDAT- 2019/06/08 06:00 MHDA- 2020/05/19 06:00 CRDT- 2019/06/08 06:00 PHST- 2018/07/17 00:00 [received] PHST- 2019/05/03 00:00 [revised] PHST- 2019/05/05 00:00 [accepted] PHST- 2019/06/08 06:00 [pubmed] PHST- 2020/05/19 06:00 [medline] PHST- 2019/06/08 06:00 [entrez] AID - S0306-4530(18)30730-3 [pii] AID - 10.1016/j.psyneuen.2019.05.003 [doi] PST - ppublish SO - Psychoneuroendocrinology. 2019 Sep;107:251-260. doi: 10.1016/j.psyneuen.2019.05.003. Epub 2019 May 9.