Motherhood-induced memory improvement persists across lifespan in rats but is abolished by a gestational stress V. Lemaire, 1 J.-M. Billard, 2 P. Dutar, 2 O. George, 1 P. V. Piazza, 1 J. Epelbaum, 2 M. Le Moal 1 and W. Mayo 1 1 University Victor Segalen, INSERM U588 Institut Franc ¸ois Magendie, 146 rue Le ´ o Saignat, 33077 Bordeaux Cedex, France 2 INSERM U549 Centre Paul Broca, 2ter Rue d’Ale ´ sia, 75014 Paris, France Keywords: aging, gestational stress, hippocampus, memory, motherhood, synaptic plasticity Abstract Motherhood modifies the biology and behavior of the female, a process which prepares the mother’s cognitive systems that are needed for nurturance. It has recently been shown that motherhood enhances hippocampal-mediated spatial learning and synaptic plasticity. Deleterious and long-term effects of a stress experienced during gestation have been demonstrated on progeny. Surprisingly little is known about the effect of such stress on mothers. Here, we investigated the effect of gestational stress on the adaptive changes due to motherhood. Female rats were mated and stressed during the last week of gestation. Two weeks after weaning, they were submitted to behavioral tests or electrophysiological study. A group of females were then kept for 16 months after motherhood experience to study the long-term effect of gestational stress and motherhood on memory when they were 22 months old. We confirm that a single motherhood experience selectively increases hippocampal-mediated spatial memory during the entire lifespan of female rats and protects them from age-associated memory impairments. However, we demonstrate that a stressful experience during gestation totally abolishes the positive effects of motherhood both on spatial memory and on hippocampal synaptic plasticity (long-term potentiation). Environmental factors that induce biological vulnerability have negative effects even for fundamental biological behaviors. Introduction The long-term consequences of life events are now a major concern in neuroscience and psychopathology (Andersen, 2003) as a cause of vulnerable traits that can be revealed by environmental challenges. Moreover, environmental factors influence genetically influenced behavioral orientations (Crabbe et al., 1999; Cabib et al., 2000). Motherhood represents a major adaptive situation which submits the mother’s organism to numerous factors that induce profound altera- tions to the female’s body and brain, and influence behavior (Bridges et al., 1996). Indeed, motherhood implies unusual conditions for which competitive search for food, pup retrieval and sustaining the needs of the litter are crucial for species survival. This specific condition requires high levels of cognitive adjustments, in particular spatial learning and memory abilities (Monks et al., 2003). In rats, recent maternal experience improves hippocampal function. Female rats that experienced motherhood performed better in a radial maze than nulliparous females (Kinsley et al., 1999; Pawluski et al., 2006) and exhibited increased long-term potentiation (LTP) (Tomiz- awa et al., 2003) and hippocampal dendritic spine density (Kinsley et al., 2006). These motherhood effects are probably long lasting, providing lifelong benefits for the mother (Gatewood et al., 2005; Love et al., 2005). These adaptive effects of a motherhood experience are important topics of investigation; an abundant literature concerning the effect of perinatal events on offspring’s brain development and behavioral profile shows that perinatal stressful events and related hormonal perturbations cause long-term deleterious changes in the hippocampus of progeny both at functional and at structural levels (McEwen et al., 1999). These changes include vulnerability to age-related spatial memory dysfunction (Issa et al., 1990; Vallee et al., 1999) and alterations of hippocampal plasticity (Lemaire et al., 2000). Surpris- ingly, although a large number of investigations have addressed the influence of life events during the perinatal period on the progeny, little is known about their consequences on the mother’s behaviors other than maternal behavior (Barbazanges et al., 1996; Smith et al., 2004). An unanswered question was whether the facilitative effects of motherhood on hippocampal function can be altered by environmental stress. Thus, we evaluated the influence of a gestational stress on the mother’s subsequent cognitive and affective status and hippocampal synaptic plasticity. We report that experiencing stress during gestation can abolish the beneficial effects of motherhood on hippocampal function and that this effect persists throughout the mother’s lifespan. Moreover, we show that motherhood affects specifically hippocampal-dependent memory and not emotional state. Materials and methods Animals Housing conditions Female (3 months; 240–260 g body weight) Wistar rats (Charles River, Lyon, France) were individually housed in plastic breeding cages under standard laboratory conditions (12-h ⁄ 12-h light–dark cycle; 22 °C, 60% humidity, water and food available ad libitum). After 2 weeks of habituation to the housing conditions, 30 females were mated with sexually experienced males over a maximum of Correspondence: Dr V. Lemaire, as above. E-mail: lemaire@bordeaux.inserm.fr Received 3 August 2005, revised 18 February 2006, accepted 22 March 2006 European Journal of Neuroscience, Vol. 23, pp. 3368–3374, 2006 doi:10.1111/j.1460-9568.2006.04870.x ª The Authors (2006). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd