Lactation-Induced Reduction in Hippocampal Neurogenesis is Reversed by Repeated Stress Exposure K.M. Hillerer, 1,2 I.D. Neumann, 1 S. Couillard-Despres, 3 L. Aigner, 4 * and D.A. Slattery 1 ABSTRACT: The peripartum period is a time of high susceptibility for mood and anxiety disorders, some of which have recently been associated with alterations in hippocampal neurogenesis. Several factors including stress, aging, and, perhaps unexpectedly, lactation have been shown to decrease hippocampal neurogenesis. Intriguingly, lactation is also a time of reduced stress responsivity suggesting that the effect of stress on neuro- genic processes may differ during this period. Therefore, the aim of the present study was to assess the effect of repeated stress during lactation [2 h restraint stress from lactation day (LD) 2 to LD13] on brain weight, hippocampal volume, cell proliferation and survival, and on neuronal and astroglial differentiation. In addition to confirming the known lactation- associated decrease in cell proliferation and survival, we could reveal that stress reversed the lactation-induced decrease in cell proliferation, while it did not affect survival of newly born cells, nor the number of mature neu- rons , nor did it alter immature neuron production or the number of astro- glial cells in lactation. Stress exposure increased relative brain weight and hippocampal volume mirroring the observed changes in neurogenesis. Interestingly, hippocampal volume and relative brain weight were lower in lactation as compared to nulliparous females under nonstressed conditions. This study assessed the effect of stress during lactation on hippocampal neurogenesis and indicates that stress interferes with important peripartum adaptations at the level of the hippocampus. V C 2014 Wiley Periodicals, Inc. KEY WORDS: lactation; hippocampal volume; neurons; differentia- tion; corticosterone INTRODUCTION Throughout all mammalian species, motherhood is characterized by numerous neuroendocrine and behavioral adaptations. Among these, the most obvious are lactogenesis and maternal behavior, including maternal care and aggression (Walker et al., 1995; Neumann, 2001; Russell et al., 2001; Hillerer et al., 2012). However, in addition to changes directly associated with reproductive functioning, a host of important behavioral and physiological alterations occur (Walker et al., 1995; Carter et al., 2001; Neu- mann, 2001, 2003), with decreased anxiety (Altemus et al., 1995; Carter et al., 2001; Heinrichs et al., 2001) [and see (Slattery and Neumann, 2008) for review] and increased basal cortisol/corticosterone (CORT) levels amongst the most prominent. The lat- ter alteration is related to the presence of nursing pups (Stern et al., 1973; Walker et al., 1995) and has been directly correlated with the concomitant decrease in hippocampal neurogenesis observed during the first postpartum weeks (Leuner et al., 2007). In addition to the peripartum-associated hypercorti- cism/hypercortisolism, there are numerous alterations that act in concert to decrease the response of the HPA axis to external stressors (Altemus et al., 1995; Heinrichs et al., 2001; Brunton et al., 2008). This raises the intriguing possibility that stress during the peripartum period may affect neurogenesis in a differ- ent fashion to that observed in male and female (nul- liparous) rodents. Thus, it has repeatedly been demonstrated that exposure to a variety of stressors decreases hippocampal cell proliferation and survival in males, and cell survival in females (Gould et al., 1997, 1998; Lucassen et al., 2001; Pham et al., 2003; Hillerer et al., 2013). Such stress-related alterations in neurogenesis have been posited to play a crucial role in the etiology of anxiety and depression (Fuchs, 2007; Snyder et al., 2011). Moreover, there is a grow- ing body of evidence suggesting that antidepressants mediate their effects, at least in part, by increasing hippocampal neurogenesis (Hanson et al., 2011; Snyder et al., 2011). In addition, numerous sex differ- ences in various aspects of hippocampal neurogenesis, under both basal and stress conditions, have been reported (Galea et al., 2008; Hillerer et al., 2013). The peripartum period is a time of high susceptibility for mood and anxiety disorders (Robertson et al., 2004; Beck, 2006; Lonstein, 2007; Bridges, 2008) and stress during the peripartum period is one of the most prominent risk factors to develop postpartum mood disorders (Robertson et al., 2004). Therefore, it may be hypothesized that alterations in hippocampal 1 Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany; 2 Department of Obstetrics and Gynaecology, Salzburger Landeskrankenhaus (SALK), Paracelsus Medical University, Salzburg, Austria; 3 Institute of Experimental Neuroregenera- tion, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Para- celsus Medical University, Salzburg, Austria; 4 Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria Grant sponsor: the Deutsche Forschungsgemeinschaft; Grant number: DFG SL141/4-1; Grant sponsor: the European Union’s Seventh Frame- work Programme HEALTH-F2-2011-278850 (INMiND); Grant number: FP7/2007-2013; Grant sponsors: Bavarian State Ministry of Sciences, Research and the Arts, the state of Salzburg. *Correspondence to: Ludwig Aigner, Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria, Strubergasse 21, 5020 Salzburg, Austria. E-mail: ludwig.aigner@pmu.ac.at Accepted for publication 31 January 2014. DOI 10.1002/hipo.22258 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). V C 2014 WILEY PERIODICALS, INC. HIPPOCAMPUS 00:00–00 (2014)