Epilogue

The aim of the present paper was to give a comprehensive overview of the differences in the stress system between different strains of rats. Although many different strains of rats have been used in endocrinological and neurobiological research, few large-scale studies have investigated strain differences. Most of the studies have concentrated on investigating the differences between two strains of rats (like F344 vs. LEW or SHR vs. WKY rats) or on two selection lines (like APO-SUS vs. APO-UNSUS rats). Nevertheless, this overview shows that large differences exist in both the HPA axis and the ANS stress system. Moreover, there are clear differences in the reactivity of both systems. Thus, whereas SHR rats show an exaggerated ANS response to stress, they show a relatively normal HPA axis response. Likewise, although LEW rats have a diminished HPA axis response their ANS system seems to be functioning relatively normal. This indicates that, although the two systems clearly work in a coordinated manner, they nevertheless use separate neuronal substrates.

One important issue, which has not been addressed yet, is the question why the strains show such clear differences. It seems obvious that genetic factors are involved in these strain differences. Given our limited knowledge of the rat genome, molecular genetic studies have not been performed to any great extent. One way of investigating the importance of genes is by cross breeding different strains. Sarrieau and his colleagues compared BN, F344 and the F1 offspring from a BNxF344 cross breed (Sarrieau et al., 1998). They showed that F344 rats have a significantly higher plasma corticosterone and plasma prolactin response to stress than BN rats. The BNxF344 hybrids have corticosterone levels similar to the BN rats, but significantly lower than the F344 rats. On the other hand, the prolactin levels of the hybrids are similar to the F344 rats and much higher than BN rats. Similarly, the relative adrenal weight is significantly higher in the BN rats than in the F344 or the hybrid rats. This is a strong indication that different genes are involved in these parameters.

However, it is important to realise that results from breeding experiments do not necessarily point to the involvement of genes. For instance, the reduction in corticosterone levels seen in BNxF344 rats, as compared to F344 rats may be ascribed to the introduction of specific BN genes, but it might also be that the reduction is due to the postnatal maternal influence of the BN rats. One way to resolve this issue would be to compare BNxF344 rats reared by a BN mother with BNxF344 rats reared by an F344 mother. There is ample evidence that maternal influences play an important role in determining the stress regulation of the offspring. Early manipulations such as handling or maternal separation/deprivation are known to shape the HPA axis response of the offspring

((Levine, 1994), see chapter____). An alternative approach to investigate the role of maternal factors is cross fostering, in which the rats from one strain are raised by another strain. Ideally, such research also includes a so-called in-fostered group in which pups are raised by other mothers, but from the same line. Using this approach, it was shown, for instance, that the difference in startle response between male LEW and F344 rats is reduced by cross-fostering. Likewise the differences in corticosterone response to a lipopolysaccharide injection is reduced by cross-fostering, though only in females (Gomez-Serrano et al., 2001). Interestingly, other phenomena, such as the inflammatory response to carrageen appear to be independent of the early rearing environment (Gomez-Serrano et al., 2002). It is surprising that so far, very few studies have investigated the influence of variations in maternal behaviour in HPA axis-related phenomena (except the studies of maternal deprivation and maternal separation mentioned above). One notable exception is the work of Micheal Meaney and his group who have studied the influence of maternal behaviour on HPA axis parameters. They separated on the basis of their maternal behaviour in so-called high licking/grooming, arched-back nursing (LG-ABN) and low LG-ABN, and continued to show that this maternal behaviour determined the behaviour and stress-responsivity of the offspring. As adults the offspring of high LG-ABN mothers had a significantly reduced plasma ACTH and corticosterone response to restrain stress (Liu et al., 1997). In addition, these rats also showed a significant increase in hippocampal mRNA expression for GR, an enhanced negative feedback sensitivity of the HPA axis and decreased PVN mRNA levels of CRF. In subsequent studies the authors have shown that these rats also differ in a wide variety of other behavioural and biochemical parameters (Francis et al., 1999, 2000; Caldji et al., 2000). We recently also investigated the effects of maternal behaviour in APO-SUS and APO-UNSUS rats. Cross-fostering was shown to reduce the differences in adult sensitivity to apomorphine, specifically by reducing the sensitivity in APO-SUS rats. APO-UNSUS rats do not differ in apomorphine susceptibility after being cross-fostered to APO-SUS mothers (Ellenbroek et al., 2000). It remains to be investigated whether cross-fostering also affects the differences in the HPA axis between APO-SUS and APO-UNSUS rats.

In contrast to the relative lack of cross-fostering studies related to the HPA axis, there have been many studies on the relation between maternal factors and the ANS, especially with the SHR and the WKY rats. Most of the studies clearly show that the blood pressure of SHR being raised by

WKY rats is significantly reduced compared to SHR raised by their own mother, or mothers of other SHR litters (Cierpial and McCarty, 1987; Cierpial et al., 1990a; McCarty and Lee, 1996). A similar reduction in blood pressure is also seen when SHR are reared by normotensive SD rats (Cierpial and McCarty, 1991). SHR mothers show much more licking and nursing behaviour and spend much more time with the rat pups than WKY mothers, and this behaviour changes when pups are cross-fostered, suggesting that the maternal behaviour may be a crucial factor in determining the long-term physiological development (Cierpial et al., 1990b).

In conclusion, the present review shows that clear strain differences exist in both the HPA axis as well as the ANS. So far most evidence indicate that hyperactivity in the HPA axis is independent of the hyperactivity in the ANS system. In contrast to the wealth of publications on strain differences, very few authors have investigated the origin of these differences. Although we know from other sources that genetic and early environmental factors play an important role in determining the stress response in adulthood, few studies have so far been undertaken to identify the relative contribution of these factors in determining strain or line differences. Given the fact that alterations in the stress response play an important role in many psychiatric and neurological diseases, the differences seen between strains may prove to be a valuable tool for developing good animal models for diseases such as depression, schizophrenia or anxiety disorder.

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