Maternal sleep deprivation inhibits hippocampal neurogenesis associated with inflammatory response in young offspring rats Qiuying Zhao a , Cheng Peng b , Xiaohui Wu a , Yubo Chen a , Cheng Wang a , Zili You a, ⁎ a School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China b State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China abstract article info Article history: Received 31 October 2013 Revised 8 April 2014 Accepted 14 April 2014 Available online 24 April 2014 Keywords: Sleep deprivation Pregnancy Offspring Neurogenesis Microglial activation Inflammatory response Although sleep complaints are very common among pregnant women, the potential adverse effects of sleep disturbance on the offspring are not well studied. Growing evidence suggests that maternal stress can induce an inflammatory environment on the fetal development. But people are not sure about the consequences of prenatal stress such as the inflammatory responses induced by maternal sleep deprivation (MSD). In the present study, we investigated the effects of MSD on long-term behavioral and cognitive consequences in offspring and its underlying inflammatory response pathway. The pregnant Wistar rats received prolonged sleep deprivation (72 h) on gestational day (GD) 4, 9, and 18, respectively. The post-natal day (PND) 21 offspring showed impaired hippocampus-dependent spatial learning and memory in the Morris Water Maze task and anhedonia in sucrose preference experiment. Quantification of BrdU + and DCX + cells revealed a significant decrease in hippocampus neurogenesis in prepuberty offspring, especially for the late MSD (GD 18) group. Real-time RT-PCR showed that after MSD, the expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNFα) increased in the hippocampus of offspring on PND 1, 7, 14 and 21, whereas anti-inflammatory cytokine IL-10 reduced at the same time. Immunoflu- orescence found that the cells of activated microglia were higher in the brains of MSD offspring. Taken together, these results suggested that the MSD-induced inflammatory response is an important factor for neurogenesis impairment and neurobehavioral outcomes in prepuberty offspring. © 2014 Elsevier Inc. All rights reserved. Introduction Probably due to pregnancy-associated anatomic, physiological and hormonal changes, women in pregnancy are at particular risk of sleep deprivation or restriction (Pien and Schwab, 2004). The quality of sleep usually deteriorates with the increasing gestational week (Kizilirmak et al., 2012). Recently there has been a growing research interest in the relationship between maternal sleep deprivation (MSD) and develop- ment of short- and long-term health disorders of their offspring. Research suggested that MSD can lead to several harmful consequences to their children, and can damage the mother-infant relationship (Pires et al., 2010). It is found to cause a reduction in adrenal weight and ambulatory behavior in pups (Suchecki and Palermo Neto, 1991). Rapid eye move- ment sleep deprivation in pregnant rats can cause major impairment of masculine behavior in male offspring during adulthood (Velazquez- Moctezuma et al., 1993). Sleep restriction during pregnancy may lead to renal morphologic and functional alterations in young offspring (Thomal et al., 2010). MSD is also found to cause anxiety behaviors (Calegare et al., 2010) and alter sexual behavior of the F1 offspring (Alvarenga et al., 2013). Though sleep deprivation has been shown to cause biochemical and behavioral changes in offspring (Calegare et al., 2010), mechanisms underlying such effects remain largely unknown. Previous studies have demonstrated that gestational stress, including MSD, has long-lasting effects on the HPA axis in the offspring (O'Keane et al., 2012). Maternal stress also increases the inflammatory response in their offspring, which may increase the risk of schizophrenia, autism and bipolar disorder (Andersen and Teicher, 2009; Bale, 2009). More specifically, it is suggested that secretion of inflammatory cytokines, such as IL-1β and IL-6, mediates the neurodevelopmental effects on the offspring (Ashdown et al., 2006; Chang et al., 2010; Meyer et al., 2008). Neurogenesis from neural progenitor cells in the brain is clearly established in two regions including the dentate gyrus (DG) of the hippocampus and the subventricular zone of the lateral ventricle (Gould, 2007). Here, the environment of neural stem cells (NSCs) composed of neighboring cells and soluble factors regulates their prolif- eration and differentiation (Gage, 2002). Among the factors, microglia, the resident macrophages of the brain, is one of the most important elements (Sierra et al., 2010). Microglial activation and secretion of inflammatory cytokines play a central role as modulators of the NSC microenvironments (niches) in different processes, such as proliferation, Neurobiology of Disease 68 (2014) 57–65 ⁎ Corresponding author. Fax: +86 28 83208838. E-mail address: youzili@uestc.edu.cn (Z. You).Available online on ScienceDirect (www.sciencedirect.com). http://dx.doi.org/10.1016/j.nbd.2014.04.008 0969-9961/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi