Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus

“Firstly, neurogenesis [26,28,34,41,65,71] and PSA-NCAM [8,21] have been shown to facilitate memory processes and we have recently demonstrated that the extent of memory dysfunction in aged rats is quantitatively correlated to hippocampal neurogenesis.”

“, 1999) and alterations of hippocampal plasticity (Lemaire et al., 2000).”

“Previous studies have indicated a tight correlation between neurogenesis and learning performance (Lemaire et al., 2000; Mohapel et al., 2005), and fewer new-born neurons result in poorer navigation learning and memory (Drapeau et al., 2003; Kempermann, 2002; Kempermann and Gage, 2002).”

“While studies have demonstrated the negative effects of prenatal stress on the development and survival of hippocampal neural precursors, this work has primarily focused on males (Coe et al. 2003; Fujioka et al. 2006; Lemaire et al. 2000; Lemaire et al. 2006; Van den Hove et al. 2005).”

“In accord with this hypothesis, a variety of early-life stressors can induce long-lasting changes in hippocampal corticosteroid receptor expression and HPA reactivity, heightened anxiety, and hippocampus-dependent memory deficits that persist into adulthood (Barbazanges et al., 1996; Vall ee et al., 1999; Lemaire et a…”

“In future studies, we plan to use variable stressors and stressors starting on GD 14, which may produce stronger prenatal stress effects (Koenig et al., 2005; Lehmann et al., 2000; Lemaire et al., 2000; Vallée et al., 1996).”

“…malnutrition leads to impaired cognitive functioning associated with disrupted hippocampal neurogenesis (Abbink, Naninck, Lucassen, & Korosi, 2017; Lemaire, Koehl, Le Moal, & Abrous, 2000; Loi, Koricka, Lucassen, & Joels, 2014; Matos, Orozco-Solís, de Souza, Manhães-de-Castro, & Bolaños-Jiménez,…”

“dysregulation (18, 21, 22, 24-26), impaired neural development (27), cognitive deficits (27-29) and aberrant social behaviours (30-33) in the offspring.”

“For example, combining etiologically relevant genetic mutations with environmental factors such as stress [63,66], cannabis exposure [21,48] or viral infections [13,90] offers promising solutions in increasing the power and construct validity of GEI mouse models [4].”

“2006), a reduced adult neurogenesis in the hippocampal dentate gyrus (Lemaire et al. 2000 ; Morley-Fletcher et al. 2011 ; Zuena et al. 2008) and biochemical changes that reflect abnormalities of synaptic transmission and plasticity in the hippocampus (Mairesse et al.”

“Conversely, glucocorticoids and stress, which inhibit neurogenesis, deteriorate learning and memory (Gould et al., 1997, 1998; Krugers et al., 1997; Lemaire et al., 2000).”

“The decreased cognitive pro- ficiency of prenatally stressed animals could be due to diminishedNMDA receptor function or compromised hippocampal neurogenesis (Lemaire et al. 2000; Mandyam et al. 2008).”

“The production and survival of these neurons in newborn rats apparently contribute to neuroplasticity and to a variety of hippocampus-related functions, including learning and memory (Lemaire et al., 2000; Lu et al., 2003; Snyder et al., 2001; van Praag et al., 1999a,b).”

“These abnormalities include decreased neurogenesis and decreased density of granule cells in the hippocampus (Lemaire et al. 2000), decreased LTP and enhanced LTD in hippocampal CA1 region (Son et al. 2006; Yang et al. 2006), and reduced NR2A and NR2B subunits of NMDA receptor in hippocampus (Son…”

“For example, gestational exposure to prenatal stress or stress hormones contributes to deficits in hippocampal structure and function, as well as the neurotransmitter and immune systems (Lemaire et al., 2000; Bellinger et al., 2008; Marques et al., 2013) .”

“Lemaire et al. (2000) reported a reduction in the number of granule cells within the hippocampal dentate gyrus of prenatally stressed rats measured 28 days postnatally.”

“Third, the diminished learning capacity in Tg mice indirectly decreases the proliferation of hippocampal progenitor cells, because it is reported that hippocampal learning can stimulate the proliferation of hippocampal progenitor cells [19].”

“Negative early-life experiences can also have a negative impact on adult hippocampal neurogenesis and function (Karten et al 2005; Lemaire et al 2000; Mirescu et al 2004).”

“Given the numerous studies that show a correlation between hippocampal-dependent learning and adult hippocampal neurogenesis (Gould et al., 1999; van Praag et al., 1999; Lemaire et al., 2000; Matsumori et al., 2006; Anderson et al., 2010), it is intriguing that two recent studies, using the same nestin-Cre-mediated SI…”

“Interestingly, we and others have shown that PS (Lemaire et al., 2000) and maternal immune challenges (Meyer et al.”

“the ensuing behavioral and physiological stress responses [7], studies in animal experiments also suggest that prenatal stress impairs brain development, strengthens behavioral abnormalities and provokes neurological diseases such as depression and schizophrenia in offspring [8,9].”

“Indeed, a decrease in hippocampal cell neurogenesis in the dentate gyrus and impairment in the hippocampalrelated spatial tasks in the prenatal restraint stress model of depression were observed [22].”

“Animal models that reproduce many of the features of chronic stress or adverse experiences during early life include prenatal stress (PS) exposure (Lemaire et al., 2000), acute maternal deprivation (MD) procedures (de Kloet et al., 2005b), chronic or periodic maternal separation (MS) models…”

“The decreased cell proliferation in the dentate gyrus has also been found in adolescent rat and non-human primate offspring [2,4].”

“Neurogenesis in the dentate gyrus of gestationally-stressed rats is reduced compared to non-stressed rats (Lemaire et al. 2000).”

“…is a significant contributor to neurodegeneration and cognitive dysfunction in a variety of diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis (Hoozemans et al., 2009; Lindholm et al., 2006; Prell et al., 2014; Salminen et al., 2009; Zhang et al., 2013).”

“Conversely, experiments using different aged rats (Bizon and Gallagher, 2003), stress paradigms (Lemaire et al., 2000), irradiation (Madsen et al.”

“…and cognitive function, including spatial learning and memory, via changes in calcium concentration (Eichenbaum et al., 1992; McEwen, 1994; Lemaire et al., 2000; Miki et al., 2000; Eyre sis after radiofrequency exposure on the mean density in the up B: 1 h at low energy for 5 days (1.6…”

“Old females subjected to prenatal stress exhibited higher corticosterone after plus-maze exposure and had increased adrenal gland weights according to previous reports in males [28] [53].”

“…that spatial learning in both young and aged rats increases the survival of cells generated before the learning (Gould et al., 1999) but decreases the survival of cells born during the early phase of learning (Lemaire et al., 2000; Shors et al., 2001; Dobrossy et al., 2003; Drapeau et al., 2007).”

“A large body of data addresses the potential importance of neurogenesis as it relates to the hippocampal functions of learning and memory (van Praag et al. 1999a; Lemaire et al. 2000; Shors et al. 2001; Kempermann 2002; Prickaerts et al. 2004; Snyder et al. 2005; Leuner et al. 2006; Wiskott et al. 2006).”

“This ongoing neurogenesis has been involved in learning and memory in young and old rats (van Praag et al., 1999; Lemaire et al., 2000; Drapeau et al., 2003).”

“). For example, 45-min daily stress during the last week of gestation resulted in impaired spatial memory in male rats [”

“Consistent with heightened corticosterone levels, hypertrophy of the adrenals has been reported (Lemaire et al., 2000).”

“It can compromise normal t hippocampal connectivity and reduce hippocampal size, diminishing cognitive function (Lemaire et al., 2000; Szuran et al., 2000; Nishio et al., 2001).”

“Indeed, rodent studies showed that the exposure to prenatal stress may lead to reduced hippocampal neurogenesis and impaired hippocampus-based memory processes in later life (Lemaire et al., 2000; Yang et al., 2006).”

“Indeed, stress may hasten the appearance of certain neurodegenerative diseases or other pathologies [39] [40] [41] [42] .”

“For example, fetal exposure to high levels of maternal stress can result in reduced hippocampal volume (116) and decreased postnatal neurogenesis in the dentate gyrus in both rats (117) and juvenile Rhesus monkeys (118), suggesting that prenatal stress might alter the set point of cell growth in the adolescent hippoca…”

“For example, it was reported that repeated immobilization stress to pregnant rats during the last week of pregnancy produced spatial learning deficit in the offspring associated with inhibition of neurogenesis in the hippocampus [ 9 ].”

“Adverse early life experience produces persistent reductions in neurogenesis and reduced learning abilities in adulthood (Lemaire et al., 2000).”

“, 2005); whereas a reduction in adult neurogenesis is correlated with learning impairments (Lemaire et al., 2000; Drapeau et al., 2003).”

“That GC mediate disturbances in fetal and adult neurogenesis by interfering with stem cell proliferation has been established in several in vitro and in vivo experimental models, including rat embryonic NSC (Bose et al., 2010; Kim et al., 2004; Lemaire et al., 2000; Sundberg et al., 2006).”

“On the contrary, stress and aging reduce hippocampal neurogenesis and this reduction has been proposed to contribute to cognitive impairment observed in these settings [14–19].”

“Pregnant rodents that have suffered restraint stress represent a valid model of stress with neurobiological and behavioral consequences [5,6].”

“…reported that PS reduced GR density in the adult hippocampus (Henry et al., 1994, Maccari et al., 1995), altered neurogenesis in the dentate gyrus (Lemaire et al., 2000), reduced hippocampal weight (Szuran et al., 1994, Maccari et al., 2003), and induced widespread gene expression changes that…”

“While sex-specific effects of PS on anxiety (Lemaire et al., 2000; Zagron and Weinstock, 2006), depression (Frye and Wawrzycki, 2003), cognition (Lemaire et al.”

“In rodents and non-human primates, prenatal stress induces a global (i.e., not regionally-specific) decrease in HCV and inhibits local postnatal neurogenesis in regions including the dentate gyrus (Coe et al., 2003; Kawamura et al., 2006; Lemaire et al., 2000; Szuran et al., 1994).”

“For example, a number of studies showed that PS affects neurogenesis and survival of newborn neurons in the hippocampal formation of rodents and rhesus monkeys, particularly in the dentate gyrus (Coe et al. 2003; Lemaire et al. 2000; Lucassen et al. 2009; Zuena et al. 2008).”

“It was well demonstrated that similar stress protocols could lead to depressive like behavior, higher anxiety level and impaired learning and memory in their offspring (Lemaire et al., 2000; Morley-Fletcher et al., 2003; Vallée et al., 1997; Yeh et al., 2012).”

“…stress induces various structural alterations in the brain development including synaptogenesis and adult neurogenesis (Hayashi et al., 1998; Lemaire et al., 2000; Schmitz et al., 2002; Coe et al., 2003; ∗ Corresponding author at: Doctoral Program in Kansei, Behavioral and Brain Sciences,…”

“…trace eyeblink conditioning (TEC), but the results are still rather controversial (Dobrossy et al., 2003; Drapeau et al., 2003; Gould et al., 1999a; Lemaire et al., 2000; Merrill et al., 2003; Van Praag et al., 1999a), possibly caused by diff erences in species, gender and timing of BrdU…”

“For the central nervous system, effects include changes in learning and memory and other behavioral dysfunctions (Lemaire et al. 2000; Lordi et al. 2000; Meek et al. 2000; Szuran et al. 2000; Fumagalli et al. 2007).”

“In adulthood, prenatal stress has been associated with anxious behavior [11, 12], decrease in synaptic plasticity [13], and impairments in learning and memory [12, 14, 15], all of which are conditions that support etiological relationships between prenatal stress and some neuropsychiatric diseases.”

“These stem cells or “neural progenitor cells” are located within the dentate gyrus, a component of the larger hippocampus [12], which is part of the greater limbic circuit which includes the fimbriae, fornices, amygdala, and parahippocampal gyrus [13, 14].”

“…compounds and/or hormonal and growth factor imbalance during vulnerable periods, have been suggested to result in altered epigenetic programming with possible disease risks in the adult (Rice and Barone 2000; Godfrey and Barker 2000; Lemaire et al. 2000; Weisinger et al. 2001; Napoli et al. 2002).”

“Although the precise mechanisms involved in the deleterious effects of prenatal stress on hippocampal neurogenesis and the resistance of bulbar neurogenesis to the same life events are not elucidated, one likely candidate is the HPA axis, which is hyperactive in prenatally-stressed animals [21,22], and more particular…”