Maternal care determines rapid effects of stress mediators on synaptic plasticity in adult rat hippocampal dentate gyrus

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Abstract

Maternal care in the rat influences hippocampal development, synaptic plasticity and cognition. Previous studies, however, have examined animals under minimally stressful conditions. Here we tested the hypothesis that maternal care influences hippocampal function differently when this structure is exposed to corticosteroid and noradrenergic hormones, which are elevated during the early phase of a stress response. In the adult male offspring of Long-Evans dams characterised as high or low in maternal care (high LG and low LG) we (1) examined basal dendritic morphology in the dentate gyrus by Golgi staining; (2) investigated rapid modulation of in vitro long term-potentiation (LTP) in the dentate gyrus by glucocorticoid and β-adrenergic stimulation; (3) examined hippocampal and amygdala-dependent learning under stress using contextual and cued fear conditioning. We found differences in hippocampal dentate gyrus morphology in adult offspring of high and low LG mothers, with less dendritic complexity in low LG offspring. Under basal conditions LTP was lower in slices from low compared with high LG offspring. Hippocampal LTP was rapidly increased by either corticosterone (100 nM) or isoproterenol (1.0 μM) in low LG offspring, suggesting improved dentate plasticity during stress. This was mirrored in hippocampal but not amygdala-dependent learning, as low LG offspring showed enhanced contextual but not cued fear conditioning. We suggest that decreased pup LG during postnatal life may be adaptive in high-threat environments, potentially enhancing hippocampal function in the offspring under conditions of adversity.

Introduction

The quality of parent–child relationships in humans predicts vulnerability to psychopathology in adulthood, an effect that may be mediated by the effects of parental care on the development of individual differences in stress responses (Dozier et al., 1999, Parker, 1983, Rapee, 1997). In the rat, variations in maternal care directly influence development of corticolimbic systems that regulate endocrine and emotional responses to stress (Caldji et al., 2003, Caldji et al., 1998, Champagne and Meaney, 2006, Francis et al., 1999, Liu et al., 1997, Toki et al., 2007, Weaver et al., 2004, Zhang et al., 2005). Thus, the adult offspring of mothers that exhibit higher levels of pup licking/grooming (LG; i.e., high LG mothers) show modest hypothalamic-pituitary-adrenal (HPA) responses to acute stress, attenuated fearfulness in response to novelty and reduced expression of active defensive responses to a threatening stimulus (Menard & Hakvoort, 2007). The offspring of low LG mothers appear more ‘reactive’ to adversity than those of high LG dams.

Cognitive function in the rat is also affected by maternal care. The adult offspring of high compared to low LG mothers show improved performance on tests of spatial learning and memory, notably the Morris water maze, and tests of object recognition (Bredy et al., 2004, Liu et al., 2000, Toki et al., 2007). These tests reflect hippocampal function, and subsequent studies revealed evidence of greater hippocampal expression of glutamate receptor subunits and hippocampal synaptic plasticity in the offspring of high LG mothers (Bredy et al., 2003, Broadbent et al., 2004, Champagne et al., 2008). However, the improved performance of the high LG offspring on tests of spatial and object recognition learning occurred under relatively low stress conditions in which animals were extensively habituated to the testing conditions to diminish the stress that may otherwise be experienced in such tasks. If the maternal signal associated with enhanced stress reactivity (i.e., decreased pup LG) is associated with an adaptive phenotypic profile that ‘prepares’ the animal to function under conditions of adversity (Meaney, 2001, Zhang et al., 2005) then the offspring of low LG mothers might show enhanced cognitive performance under conditions of increased threat.

Recent findings focusing on synaptic plasticity in the CA1 area support this view (Champagne et al., 2008). Corticosterone, through a delayed (presumably gene-mediated) mechanism, decreased hippocampal LTP in slices prepared from the offspring of high LG mothers, but significantly enhanced LTP in slices from low LG mothers. However, these studies examined only CA1 responses several hours after and not during a pulse of corticosterone. Moreover, it is clear that the dentate gyrus is also highly sensitive to stress (Kavushansky et al., 2006, Vouimba et al., 2007) and plays a major role in cognitive performance during stress, such as in contextual fear conditioning (Bredy et al., 2004, Hernandez-Rabaza et al., 2008, Liu et al., 2000, McHugh et al., 2007, Nakashiba et al., 2008, Toki et al., 2007). We here tested the hypothesis that hormonal conditions such as occur during the early phase of a stress response favour enhanced dentate function in low LG rats compared to high LG rats using both in vitro and in vivo approaches. Our initial studies examined the basal state of dentate structure using Golgi staining to define dendritic morphology. Subsequent in vitro studies examined rapid modulation of LTP, a model of the cellular mechanism of learning and memory (Bliss and Collingridge, 1993, Malenka and Nicoll, 1999), in the dentate gyrus by glucocorticoid and β-adrenergic stimulation at the time of LTP induction in high and low LG rats. Glucocorticoid and β-adrenergic systems are activated by stress and modulate plasticity in the hippocampus (Pu et al., 2007, Pugh et al., 1997, Roozendaal et al., 2008, Sandi, 1998) but also in other limbic areas, most notably the amygdala nuclei (Roozendaal et al., 2006). We used contextual fear conditioning to examine whether the influence of maternal care on stress hormone-LTP interactions in the dentate in vitro is translated into effects in vivo in a hippocampal-dependent form of learning that occurs under stressful conditions. The dependence of the effect on the hippocampus rather than the amygdala was examined through comparison to cued conditioning, a non-hippocampal, amygdala-dependent task (Phillips & LeDoux, 1992).

Section snippets

Animals

Long-Evans dams (Charles River) were mated at McGill University, Canada and Leiden University, the Netherlands. After mating, females were singly housed with ad libitum access to food and water in a 12 h light/dark cycle (lights on at 08:00). Litters were completely undisturbed from the day of parturition until postpartum day 7. Maternal behaviour was observed on days 1–6 postpartum, every 3 min during 75 min observation periods, of which two occurred in the dark phase (7:00, 20:00) and three in

Dendritic morphology

Morphological analysis of dentate gyrus neurons revealed greater dendritic arborisation in adult offspring of high compared to low LG mothers (typical examples in Fig. 1A). Although total dendritic length (Fig. 1C) was not different, dendrites of high compared to low LG rats had significantly more branching points (t = 1.88, df = 12, p = 0.04; data not shown). Moreover, the dendritic complexity index, a measure of dendritic arborisation, was greater in high than low LG rats (t = 1.91, df = 12, p = 0.04;

Discussion

These findings reveal that the effect of stress hormones on dentate plasticity is dependent upon postnatal maternal care. Likewise, variations in maternal care determine hippocampal-dependent learning in a stressful context. Taken together, these findings are consistent with the idea that variations in maternal care produce specific forms of phenotypic diversity in the offspring, the function of which is further determined by the environmental context in later life.

Concluding remarks

Maternal effects on phenotypic plasticity might ‘prepare’ the offspring for prevailing environmental conditions (Hinde, 1986, Meaney, 2001, Rossiter, 1998, Zhang et al., 2005). Importantly, chronic stress decreases pup LG in lactating rats (Champagne and Meaney, 2006, Smith et al., 2004). This pattern is consistent with studies performed with simpler organisms showing that environmental adversity decreases parental investment in the offspring and alters phenotypic variation in defensive

Acknowledgments

We thank Ger Ramakers and Chris Pool from the Netherlands Institute for Neuroscience for their help and for providing software used in the morphological analysis and Shakti Sharma for radioimmunoassay of plasma corticosterone. This work was supported by HFSP Grant #RGP0039/2006 to M.J.M.

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    Both authors contributed equally to this work.

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