Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice
Introduction
Early life stress (ELS) impacts neural development and significantly increases the lifetime risk for the development of cognitive and affective pathology (Felitti et al., 1998, Anda et al., 2006). The effects of ELS on the development and functioning of the underlying neural circuitry is thought to be a major contributing factor increasing risk for adverse outcomes. Currently, the predominant focus has been on the effect of ELS on the birth, survival, and morphology of cells. In the developing hippocampus and cortex, ELS or stress hormone exposure lead to: diminished cell proliferation and increased cell death (Gould et al., 1991c, Gould et al., 1991b, Tanapat et al., 1998), enhanced turnover and progressive loss of dendritic arbors and spines (Chen et al., 2008, Liston and Gan, 2011, Chen et al., 2013), decreased synaptic density (Teicher et al., 2006), and reduced volume in adolescence and adulthood (Vythilingam et al., 2002, Frodl et al., 2010). These results are consistent with observations in the adult animal, where chronic stress leads to dendritic simplification, spine loss, cell death, and suppressed neurogenesis (Gould et al., 1991a, Radley et al., 2004, Wood et al., 2004, Hajszan et al., 2009). Based upon these findings, it has been argued that ELS serves to truncate the process of neural development, with adverse behavioral outcomes often being characterized as developmental delays.
This early silencing of growth has also been linked with what appears to be precocious behavioral maturation. For example, in rodents, priming of the developing brain with stress hormones leads to an earlier emergence of defensive behaviors (Takahashi, 1995, Takahashi, 1996). ELS in the form of manipulations of maternal care or stress hormone exposure leads to a precocious switch from appetitive to aversive learning in a fear conditioning paradigm (Sullivan et al., 2000, Moriceau and Sullivan, 2004) as well as adult-like forms of fear extinction in juvenile animals (Callaghan and Richardson, 2014). Recent work indicates that ELS may also alter neurobehavioral development in humans, as individuals exposed to institutionalized rearing were found to have an earlier expression of adult-like functional connectivity between frontal and limbic brain regions compared with age matched controls (Gee et al., 2013). While these studies provide elegant demonstrations that ELS contributes to what appear to be more mature patterns of behavior and neural activity, these studies did not directly assess the effects of ELS on the ontogeny of neural maturation. It is unlikely that the earlier halting of neurogenesis or effects on cell death are solely supporting the accelerated profile of behavioral development observed by others. Here, we sought to test if in addition to truncating processes of cell birth, ELS impacts the rates of neural maturation, and if so, what mechanisms might be driving such effects.
To test if ELS impacts rates of maturation, we examined a mouse model of ELS, fragmented maternal care (Rice et al., 2008), and focused on the hippocampus, an area that is highly sensitive to stress, and an area that has reliably been implicated in the development of stress-associated pathology. We used a cross-sectional dense sampling approach throughout early development (4 to 50 days of age) in which we measured developmental changes in hippocampus-dependent contextual fear, gene expression, and immunohistochemical markers of development at short intervals (~ 4–10 days, Fig. 1). This approach allowed us to directly examine the effects of ELS on the ontogeny of both neural and behavioral measures of development within the same circuit.
Here, ELS led to an earlier emergence of the timed developmental suppression of hippocampus-associated fear behavior in a fear-conditioning paradigm. Using gene expression analyses and immunohistochemistry, we found that ELS led to the earlier onset and expression of biomarkers associated with neural maturation in the hippocampus and an earlier silencing of biomarkers associated with cell proliferation and differentiation. Taken together, these data provide strong support for the hypothesis that, in the hippocampus, ELS leads to a precocious switch from processes of growth to earlier neural and behavioral maturation.
Section snippets
Subjects
Male C57BL/6N mice were bred in house, had ad libitum access to food and water, and were housed on a 12 h:12 h light:dark cycle. All animal procedures were approved by the Brown University Institutional Animal Care and Use Committee and consistent with the guide for the care and use of animals in research.
Fragmented maternal care
Four days following birth of a litter, the dam and pups were transferred from their standard home cage, to a home cage with a wire mesh floor and a 2 × 4 cm cotton nestlet as their only source of
ELS elevates basal stress hormone levels and delays somatic growth
Consistent with previous results in mice (Rice et al., 2008), we found that ELS led to elevated basal serum corticosterone levels compared with control animals (ANOVA, corticosterone, F(1,25) = 9.67, p < 0.01, η2 = 0.036; Fig. 2A). This effect emerged following the completion of the ELS manipulation, at 16 days of age (post hoc, p < 0.05, d = 2.5), and was no longer present when mice reached adulthood (post hoc, p > 0.05, d = 0.2; Fig. 2A). ELS reared pups gained less weight and weighed less than control
Discussion
Here, we demonstrate that ELS, in the form of fragmented maternal care, leads to an accelerated profile of hippocampal behavioral development using a fear conditioning paradigm, as well as precocious expression of measures of maturation in the hippocampus. These findings are paired with the observation that ELS results in a more rapid developmental decline in the expression of markers of neuronal proliferation and differentiation in this same structure. Taken together, these novel findings
Conclusions
In summary, the studies presented here represent the first direct demonstration that ELS is associated with an acceleration of both behavioral and neural maturation of the hippocampus. Such findings reveal novel effects of ELS on processes of growth and maturation and identify potential mechanisms regulating these effects. Such insights could be important for informing the way we think about stress effects on developmental trajectories and possible mechanism underlying later development of
Conflict of interest
The authors declare no competing interest.
Acknowledgements
This work was supported by the Brown Institute for Brain Sciences and Robert and Nancy Carney gift for scientific innovation (K.G.B.), Brain and Behavior Research Fund NARSAD Young Investigator Award (K.G.B.). We thank Jason Gray and Francis Lee for their careful reading and comments on this manuscript, Dima Amso for her assistance in statistical analysis, and Joan Stabila for technical analysis.
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