Stressful childhood experiences in humans are able to predict a number of stress-dependent life outcomes, increasing the risk of depression, substance abuse, and suicide (McEwen, 2003). This effect has been demonstrated in rodent models as well, where the causal role of childrearing can be isolated from possible genetic effects through cross-fertilization designs. There is maternal variation in levels of licking and grooming (LG), elicited from the pup either by tactile stimulation of the dam’s stout or ultrasonic vocalizations (Stern, 1997). These individual differences in levels of LG modulate the pup’s development of hypothalamic-pituitary-adrenal (HPA) stress responses (Weaver et al, 2004). As adults, rats reared by high LG dams exhibit diminished HPA responses to stress and are less fearful than those reared by low LG dams (Francis et al, 1999). Moreover, when exposed to a novel environment, the adult offspring of high LG dams spend more time eating and start eating more quickly than those of low LG dams, indicating an increased disposition for novelty-seeking (Caldji et al, 1998). Champagne et al (2008) present evidence that these differences in maternal care affect the morphology of cells in the hippocampus, which leads to differential changes in long term potentation (LTP) when exposed to corticosterone (CORT) in vitro, as well as differences at the behavioral level. This paper will examine that evidence and propose a plausible evolutionary account of the early-environment dependent differences.
One line of inquiry that Champagne et al consider is the possibility that the neuronal morphology in the hippocampus will differ in high LG offspring as compared to low LG offspring. Using Golgi staining on random pyramidal cells in both hemispheres of the dorsal hippocampus and then performing blind quantitative analysis, they found that there are in fact significant differences between the two groups. Dendrites both on the base and the apex of the cell were longer in the high LG group compared to the low LG group, and there were more exogenous inputs (spines) in the dendrites of high LG offspring than there were in the low LG offspring. Although the migration of pyramidal cells is complete at birth, their dendrites undergo rapid sculpturing between postnatal days 3-20 (Turner et al, 1998), and it is in the early part of this critical period that the divergences based on levels of maternal LG emerge. Champagne et al also note that low LG adult rats have lower glucocorticoid and mineralocorticoid receptor (GR and MR) protein levels than high LG rats, indicating a reduction in responding to corticosterone (CORT), which affects neurons by binding to those receptors.
These morphological differences are associated with changes in the response of coronal hippocampus slices to high frequency electrical stimulation following treatment with CORT. Champagne et al measured the field excitatory postsynaptic potential (fESPS) of adult of the CA1 stratum radiatum using bipolar stimulation electrodes, comparing the baseline measures to those after pretreatment of CORT and inducement of LTP. When the vehicle treatment (VEH) was used without CORT, slices from high LG rats showed a substantial percentage increase in fESPS over baseline, but when CORT was included, this increase disappeared. The opposite was the case for the low LG rats, as VEH on its own led to only a slight increase from baseline, but CORT treatment induced a substantial increase. Since there is a strong correlation between in vitro LTP with learning and memory in rodents (Cooke and Bliss, 2006), these results indicate that there is a trade-off between learning optimally either under stressful or normal conditions, mediated by levels of LG during development.
Indeed, previous work in a water maze paradigm has shown that high LG rats have shorter latencies to find the platform on trials 2-5, indicating an improved ability to learn in a low-stress environment (Bredy et al, 2003). Champagne et al expose the other side of the trade-off by examining the ability of high LG and low LG rats to learn under a high-stress environment. They habituated rats to the testing room to control for novelty (because of Caldji et al, 1998), and then exposed rats to a contextual fear learning task. Their 1 second, 1 mA shock has been previously demonstrated to lead to a rise in circulating CORT levels, confirming that it is a potent stressor. Upon re-exposure to the context, low LG rats spent significantly more of their time in the expected freeze response as compared to high LG rats. This well controlled behavioral test allowed the authors to conclude that although low LG rats perform worse compared to high LG rats in low stress learning contexts, they perform better in high stress learning contexts.
If we make the reasonable assumptions that there is a large amount of variance in the ecological environments of the Long-Evans rat, each with different demands in terms of stress, and that the environment during development is highly correlated with the environment that rats inhabit as adults, then a plausible evolutionary account follows. At the genetic level, responding in the HPA axis is regulated at least in part through the epigenetic methylation of the exon 17 GR promoter (Weaver et al, 2004). It has been suggested that there is a “steady state” of DNA methylation and demythylation of this GR exon 17 promoter, and that this equilibrium can be shifted (Meaney and Szyf, 2005). A random mutation that causes the equilibrium to shift during development toward the methylated state in low stress environments depending upon maternal levels of LG would cause the learning and memory of the offspring to be better suited to its environment, thus increasing inclusive genetic fitness. As a result of this mutation, mothers could either be programmed to perform less LG in high stress environments or pups could be programmed to solicit less LG. Over evolutionary time, the gene(s) coding for the environmentally determined plasticity of LG would be selected for. One prediction of this account is that dams in their natural habitats should perform less LG under high stress conditions than low stress ones. If this prediction does not hold, then it is likely that the apparent trade-off in learning under different levels of CORT is a consequence but not a cause of the morphological development of rat hippocampal regions as a function of maternal LG.
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