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critically on the preceding corticosterone environment. In intact animals sustained
hypovolemia only activates CRH gene transcription, while AVP gene activation is
suppressed during the entire response (Figure 7.10; Watts and Sanchez-Watts,
1995b; Tanimura et al., 1998). This observation is consistent with reports that show
CRH as opposed to AVP secretion is suf¬cient to maintain ACTH secretion during
hemodynamic stressors (Plotsky and Vale, 1984; Plotsky et al., 1985). This situation
changes dramatically in ADX animals. Now robust AVP gene transcription accom-
panies the entire ACTH secretory episode (Figure 7.10; Tanimura and Watts,
2000). As I have just discussed, this occurs in the presence of short premature CRH
gene transcription. These data demonstrate that prior exposure to corticosterone
has a profound effect on which signal transduction pathway (CRH or AVP) is
selected during stress.
Since the AVP gene contains a GRE and that corticosterone interacts with signal
transduction pathways (Beato et al., 1995), at least part of these effects of cortico-
sterone likely occurs within the neuron itself. But because the type of stressor (and
therefore the afferent input) is critical in determining whether the AVP gene is acti-
vated in PVHmp neurons, corticosterone may also have actions on afferent path-
ways to determine when and which genes are activated (Itoi et al., 1999). Thus, in
contrast to hemodynamic stressors, some other stressors are followed by increases
in AVP hnRNA and mRNA (Herman, 1995; Kovács and Sawchenko, 1996a, b; Ma
et al., 1997; Kovács et al., 2000). Since the preceding corticosterone environment
is likely to be quite similar for all these stressors (i.e. all these studies used intact
animals), differential afferent activation would seem to be at least partly responsi-
ble for why AVP gene activation is much more apparent with some stressors (e.g.
restraint) than with others (hemodynamic stressors). Again these data support the
hypothesis that selective secretogogue gene activation is mediated by the inter-
action of PVHmp afferents and corticosterone (Figure 7.6).

Negative feedback
Does a closed-loop negative-feedback signal from corticosterone operate during
stress? One way to address this issue is to examine the dynamics of CRH gene
expression during the prolonged secretion of corticosterone that occurs during
sustained hypovolemia. If corticosterone provides a negative-feedback signal dur-
ing stress, one would expect to see CRH hnRNA and mRNA levels fall in response
to this elevated secretion. Does this occur? Two sets of observations suggest that in
fact a negative-feedback signal does act on gene expression during stress, but it is
not within a rapid (i.e. tens of minutes) time-frame. First, CRH mRNA levels do
eventually fall under these circumstances, as would be consistent with closed-loop
227 Glucocorticoids and the ups and downs of neuropeptide gene expression


negative-feedback action (Tanimura et al., 1998). However, the fact that this reduc-
tion is not accompanied by a concurrent fall in CRH hnRNA levels suggests that
under these circumstances one effect of corticosterone is to decrease CRH mRNA
half-life (Ma et al., 2001). Second, CRH gene transcription is maintained during
sustained hypovolemic stress for at least 3 h despite the presence of very high cir-
culating levels of plasma corticosterone (Tanimura et al., 1998). Similarly, Ma et al.
(1997) showed that CRH gene transcription was not reduced by a supra-physio-
logical bolus injection of corticosterone in ADX animals for at least 2 h. These
studies provide no evidence for rapid negative-feedback regulation of the type that
restrains ACTH secretion during certain stressors (Keller-Wood and Dallman,
1984), and emphasize that the mechanisms operating to regulate stressor-induced
CRH gene expression are different from those that regulate stressor-induced ACTH
secretogogue release.
What about the AVP gene? It is clear that in CRH neuroendocrine neurons, the
AVP gene is regulated very differently from the CRH gene (Kovács and Sawchenko,
1996a, b; Kovács et al., 2000; Kovacs, 1998; Ma et al., 1997; Tanimura and Watts,
1998; 2000; Ma and Aguilera, 1999). Consistent with this notion is the fact that cor-
ticosterone produces a much more rapid negative-feedback signal on AVP gene
expression than on CRH gene expression. Thus, a bolus injection of corticosterone
takes less than 15 min to reduce AVP hnRNA levels compared to the 2 h required
for CRH hnRNA (Figure 7.7; Ma et al., 1997). In the presence of corticosterone, an
AVP gene response to acute stress is much more dif¬cult to evoke than CRH
(Darlington et al., 1992; Watts and Sanchez-Watts, 1995b; Kovács and Sawchenko,
1996a, b; Kovács et al., 2000); only when corticosterone is removed before the stres-
sor do we see signi¬cant AVP transcription (Figure 7.10; Kovacs, 1998; Tanimura
and Watts, 2000), which in this case is concurrent with increased secretion (Figure
7.10).


Summary

Glucocorticoids are important regulators of neuropeptides. The original idea of
glucocorticoids functioning as a negative-feedback-response molecule, restraining
neuropeptide release and gene expression has given way to a more ¬‚exible, context-
oriented understanding of regulation. The ˜familiar™ downregulation of CRH gene
expression by glucocorticoids is actually only seen in cells in the mp part of the
PVHmp. In other cell types glucocorticoids can either upregulate CRH gene expres-
sion or have no effect.
Even within the PVH, the effects of glucocorticoids on CRH cells depend on
whether the cells are under basal or stimulated conditions. At low (basal) levels,
corticosterone acts to facilitate CRH gene transcription in rat PVH. Although an
228 A. G. Watts


absence of corticosterone results in an inability to restrain the vasopressin response
in concordance with the negative-feedback model, in contrast it also results in an
inability to sustain the CRH response.
Glucocorticoids can act directly or indirectly on CRH producing and releasing
cells. There are multiple levels of interactions between glucocorticoids and CRH;
cellular actions of glucocorticoids are highly complex and include more than
direct gene interactions. CRH synthesis (translation of CRH mRNA into CRH
peptide) and CRH release (membrane excitability) are different processes that can
be either coupled or uncoupled. CRH release can be thought of as the immediate
response to a stimulus; CRH synthesis a more long term, adaptive response. Although
CRH transcription is eventually reduced in the presence of elevated glucocorticoids,
it is not a rapid effect. CRH transcription can be maintained for hours. Mechanisms
that regulate CRH gene expression are different from those that regulate CRH
release.
Recent ¬ndings from human research and a large body of experimental evidence
from animal models support the hypothesis that excessive maternal glucocorticoid
(either endogenous or exogenous) can have organizational effects on the fetus that
have long-term consequences. These effects can have social, behavioral, and tem-
perament consequences that might be linked to alterations in the regulation of
CRH or other neuropeptides in the brain (see Chapter 8). Understanding the dif-
ferent mechanisms by which glucocorticoids can regulate neuropeptides, such as
CRH, enhances our ability to devise and test hypotheses regarding the regulation
of neural function.

Acknowledgements

Work in the author™s laboratory is supported by NS29728 and MH66168 from the
National Institutes of Health.


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