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orbital cortex. Anterior is to the left, and (b) Relationship between plasma cortisol
concentrations measured immediately prior to the PET radiotracer injection and
normalized glucose metabolism in the left amygdala for an MDD sample (n 15).
Adapted from Drevets et al. (2002)
257 Glucocorticoid facilitation of CRH in the placenta and the brain


cortisol in PTSD patients (Yehuda, 2002). Indeed, CRH has been found to be ele-
vated in CSF of PTSD patients (Bremner et al., 1997; Baker et al., 2001). Individuals
with generalized social phobia, another type of anxiety disorder, hyper-secreted
cortisol during a public performance involving a mental arithmetic test (Condren
et al., 2002). The amygdala research demonstrates a similar phenomenon. PTSD
and social phobic patients have normal resting (non-provoked) levels of amygdala
activity, but the amygdala is highly responsive to anxiety provocation (Rauch et al.,
1996; Shin et al., 1997; Schneider et al., 1999; Rauch et al., 2000).
Finally, behavioral inhibition in childhood, characterized by increased cortisol
levels and right frontal EEG recordings, is associated with increased risk for anxi-
ety disorders in adulthood (e.g. Schmidt et al., 1997; 1999a, b; Rosenbaum et al.,
2000; Biederman et al., 2001; Buss et al., 2003). Behavioral inhibition is more likely
to manifest in children whose parents are diagnosed with social phobia and
depression (Rosenbaum et al., 2000). In addition, there is evidence that infants of
mothers with mood and anxiety disorders show neural characteristics different
from those of psychiatrically healthy mothers in the absence of overt behavioral
differences. For example, infants of mothers with panic disorder show elevated
salivary cortisol and disturbed sleep although they did not show higher behavioral
reactivity, behavioral inhibition, or ambivalent or resistant attachment to the
mothers. The neurophysiological differences observed in these infants might be
important early indicators of risk (Warren et al., 2003).


Conclusions

Glucocorticoids have both permissive, suppressive and stimulatory effects on
diverse end organ systems (Sapolsky, 2000). Most well known are the suppressive
effects, particularly at the level of the PVN projections to the pituitary gland. Less
well known are the stimulatory effects on diverse tissue with regard to CRH in the
placenta and in several regions of the brain, particularly those regions involved in
emotional behavior and emotional regulation. Chronic exposure to stress or
stressful situations results in increased glucocorticoid concentrations and the facil-
itation of CRH gene expression in these regions (Schulkin et al., 1998; Dallman
et al., 2003). Animals that have higher levels of glucocorticoids as a result of selective
breeding or through glucocorticoid infusions tend to act more fearful (Jones et al.,
1992). Glucocorticoids are secreted in diverse events that require the expenditure
of energy (Dallman et al., 2003). While glucocorticoids are certainly not the mole-
cules of fear and anxiety, they are associated with fear, anxiety, and trauma “ all of
which are metabolically demanding events.
In the human placenta, while not de¬nitely demonstrated, one function of gluco-
corticoids in normal pregnancy is to make CRH available to promote the timing of
258 J. Schulkin et al.


parturition; this process can be accelerated, perhaps as the result of adverse envi-
ronmental conditions. Chronic alterations of CRH by diverse events, including
nutritional needs, hypertension and psychosocial stress (e.g. Hobel et al., 1999),
can render women vulnerable to low-birth-weight infants and preterm delivery of
their offspring. Glucocorticoids are also increased, and exposure to elevated gluco-
corticoids prenatally can alter amygdala development by increasing CRH expres-
sion in the CeA (Welberg et al., 2000). This suggests potential lifelong consequences
and vulnerabilities resulting from prenatal glucocorticoid exposure. In extra-
hypothalamic sites in the brain that underlie the behavioral regulation of fear,
CRH plays an important role in the fear response, and glucocorticoids play an
important role in sustaining fear-related behavioral responses. High cortisol levels,
due to genetic and/or early environmental factors, may induce long-lasting hyper-
excitability in central CRH gene expression. Elevated levels of CRH are tied to
increased salience of environmental stimuli (Merali et al., 2003) which can result in
hypervigilance and a vulnerability for exaggerated fear responses. Interestingly,
CRH type I receptor antagonists delay early parturition in sheep (Chan et al.,
1998) and can reduce fear-related behavioral responses in macaques and rats
(Deak et al., 1999; Habib et al., 2000), indicating another link between placental
and amygdala CRH.
The neural circuit that includes the amygdala, bed nucleus of the stria terminalis
and regions of the prefrontal cortex contributes to the behavioral regulation of
emotional responses, particularly fear. The CRH induction by glucocorticoids may
underlie the fear responses. The CRH has been localized in regions of the pre-
frontal cortex, and glucocorticoids may regulate CRH in this region (Swanson,
personal communication; unpublished observations) in addition to the amygdala
and bed nucleus of the stria terminalis.
Corticotropin-releasing gene expression can also be altered by postnatal
events (e.g. Brunson et al., 2001). Diverse experiments have suggested that gluco-
corticoids are important in adapting to fearful events, and the susceptibility of
HPA and extra-hypothalamic regions to alterations during early life may be evolu-
tionarily adaptive. In nonhuman primates, exposure to variable foraging condi-
tions has long-term effects on neuroendocrine systems (Coplan et al., 2001), and
macaques raised by peers instead of by their mothers also show long-term changes
in behavioral and neuroendocrine responses to stress. These alterations are
maladaptive in humans, and may create increased vulnerability to psychiatric
disorders.
Fear of unfamiliar objects is a basic adaptation, perhaps exaggerated in vul-
nerable individuals who have been shown to have higher levels of glucocorticoids
(which has been demonstrated in a number of species, (Kagan et al., 1988; Cavigelli
and McClintock, 2003)). Heightened levels of arousal and fear responses to strangers
259 Glucocorticoid facilitation of CRH in the placenta and the brain


and novel situations found in shy human infants also persist at least into later child-
hood. These children can have exaggerated cortisol and autonomic physiological
responses (Kagan et al., 1988; Gunnar et al., 1996; Schmidt et al., 1997). Indeed,
excessively shy children display both exaggerated startle responses and high salivary
cortisol levels (Schmidt et al., 1997). Temperamental shyness is also associated with
increased amygdala and right frontal activation (e.g. Schmidt et al., 1997; Davidson
et al., 2003). In addition, extremely shy, socially withdrawn children may be vulner-
able to anxiety disorders and perhaps to depression throughout their lives
(Hirshfeld et al., 1992; Schwartz et al., 1999). The induction of CRH gene expression
by glucocorticoids may contribute to the central state that underlies fear- and anxiety-
related behavioral responses. These events, namely the induction of elevated levels
of CRH gene expression, are adaptive in the short term; in the long run (both from
prenatal and postnatal events), they may result in long-term aberrations in CRH
gene expression and vulnerability to excessive anxious behaviors.



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