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7


Glucocorticoids and the ups and downs of
neuropeptide gene expression
Alan G. Watts
The NIBS-Neuroscience Program and Department of Biological Sciences, University of Southern California,
Los Angeles, California, CA, USA




Introduction

Neuropeptides, such as corticotropin-releasing hormone (CRH) are critical mole-
cules that act as neuromodulators throughout the central nervous system. They are
implicated in controlling a wide range of behavioral, autonomic, and neuro-
endocrine functions. Glucocorticoids are important hormones that have profound
effects on many aspects of neuronal function, including the regulation of neuro-
peptide biosynthesis. Elevated levels of maternal and fetal glucocorticoids play
important roles in the normal progression of pregnancy and fetal growth; how-
ever, they also have been implicated in many pathologies of pregnancy and fetal
development (see Chapters 3“6). Their role in regulating neuropeptides, both in
fetal and maternal brain, has been suggested as a causal link in their effects on
pregnancy and fetal development.
The proposed effects of glucocorticoids on the maternal“placental“fetal axis are
based on epidemiological evidence and experimental manipulations in animal
models. The mechanisms by which glucocorticoids regulate neuropeptide storage,
release, and gene expression, however, are not completely understood. A clearer
understanding of these processes is necessary to generate and test meaningful
hypotheses about how these mechanisms are controlled. Recent ¬ndings indicate
that glucocorticoids have variable effects on CRH regulation depending on cell
type, and intra- and extracellular factors.
Perhaps the most familiar example of glucocorticoid actions on neuropeptide
gene expression is its inhibitory actions on CRH and arginine vasopressin (AVP)
genes in neuroendocrine neurons of the hypothalamic paraventricular nucleus
(PVH). Despite the apparent simplicity of this particular effect and its importance
for controlling glucocorticoid secretion from the adrenal cortex, its cellular basis
is undoubtedly complex and remains unclear. What is known, however, is that
glucocorticoids have very different effects on CRH gene expression in other cells.
202
203 Glucocorticoids and the ups and downs of neuropeptide gene expression


For example, CRH messenger ribonucleic acid (mRNA) expression is upregulated
by glucocorticoids in the central nucleus of the amygdala and in the human pla-
centa. This means that the effects of these steroids are dependent on the particular
cellular environment in which the CRH gene is expressed.
This chapter will review our current understanding of how glucocorticoids reg-
ulate the expression of the genes that encode these important neural signals. The
regulation of the CRH gene provides a model for considering cell-speci¬c gluco-
corticoid regulation of other neuropeptides.



Glucocorticoids and their interaction with neuropeptide gene expression

For many years the in¬‚uence of glucocorticoids has been recognized as a critical
feature that inhibits the output signals of the brain and anterior pituitary (see Yates
and Maran, 1974; Dallman et al., 1987; Sapolsky et al., 2000, for reviews). More
recently, the way corticosterone regulates the expression of genes encoding the
adrenocorticotropic hormone (ACTH) secretogogues CRH and AVP has been
taken as an exemplar for how end-organ hormones contribute to the molecular
mechanisms ultimately controlling the activity within the system.
CRH and AVP are synthesized in neurons located in the medial parvicellular
(mp) (neuroendocrine) part of the PVH. They are released in a stimulus-dependent
manner into the hypophysial portal vasculature from terminals in the median emi-
nence (ME). Many studies during the last 15 years have documented powerful
inhibitory actions of glucocorticoids on the synthesis, storage, and release of CRH
and AVP in the PVHmp and ME (see Swanson and Simmons, 1989; Whitnall,
1993; Watts, 1996, for reviews). For the most part, however, this inhibition has been
considered simply as a gene-targeted negative-feedback servo-mechanism embed-
ded within the larger and more complex regulatory mechanisms operating within
the hypothalamus“pituitary“adrenal (HPA) axis (Figure 7.1). But despite the obvious
importance for glucocorticoid feedback on PVHmp gene expression to the func-
tioning of the HPA axis, the mechanisms responsible for directing this apparently
simple event remain frustratingly elusive.


Principles of negative feedback
Ever since the pioneering work of Moore and Price (1932), and Hohlweg and
Junkmann (1932), the axiom that steroid hormones constitute negative-feedback
signals has been a central tenet of endocrine physiology. Rudimentary closed-loop
feedback of the type originally developed in the 1930s for target-organ regulation
of the pituitary has remained a popular model for explaining neuroendocrine
mechanisms of homeostasis, despite the fact that the level of sophistication with
204 A. G. Watts


Neural
Brain modulation



PVH CRH neuron

CRH, AVP
ME


CRH, AVP
Hypophysial portal
vasculature



Pituitary Corticotrope

ACTH


Adrenal Adrenal cortex

Glucocorticoids ?

Other
Target
tissues
effects

Figure 7.1 A schematic view of the HPA axis. CRH neurons in the neuroendocrine PVH nucleus
release CRH and AVP into the hypophysial portal vasculature to stimulate ACTH release
from anterior pituitary corticotropes. ACTH in turn stimulates cells in the zona fasciculata
of the adrenal cortex to release glucocorticoids, which have multiple functions throughout
the body. They also exert regulatory in¬‚uences upon the actions of corticotropes, CRH
neurons, and a variety of neural circuits


which control theory could be applied to endocrinology in general (e.g. Hoskins,
1949) was raised over 50 years ago by the publication of Cybernetics (Weiner, 1948).
The concepts derived from control theory were extensively applied by Yates™s group
throughout the 1960s to explain how HPA secretory activity was regulated by
corticosterone (e.g. Yates and Maran, 1974).
The classic closed-loop feedback model posits that neuroendocrine secreto-
gogue peptides and their mRNAs, together with circulating hormone concentrations
are all maintained between upper- and lower-limit values by comparator-generated
error signals derived from the difference between set-point and actual values
(Figure 7.2(a)). As other in¬‚uences “ for example, a stressor, in the case of the HPA
axis “ move variable values outside these limits, negative-feedback signals from
the target generate the appropriate responses to return variables back between the
205 Glucocorticoids and the ups and downs of neuropeptide gene expression


120
Afferent
control




Relative levels of CRH mRNA
100




(% mean ADX value)
80
Set-point
Comparator
range
60

40
Feedback Error signal
signal
20
Glucocorticoid Circadian range
0
0 50 100 150 200 250
Glucocorticoid Plasma corticosterone
Effects
(a) (b) concentration (ng/ml)

120

100
(% mean ADX weight)




PVH
Thymus weight




80
CRH, AVP
60
Corticotrope
40
ACTH
20
Adrenal cortex
0
Glucocorticoid 0 50 100 150 200 250
Plasma corticosterone
concentration (ng/ml)
(c) (d)
Thymus

Figure 7.2 (a) The organization of a closed-loop feedback loop. The level of a target variable is
maintained between a set-point range by a ˜push“pull™ mechanism consisting of the drive
from a variety of neural afferents and the negative-feedback in¬‚uence of glucocorticoid. A
hypothetical comparator system then generates an error signal in the form of CRH and
AVP to adjust glucocorticoid levels. Although widely used to explain the way
glucocorticoids regulate the activity of CRH neurons and corticotropes, this simple system
cannot explain the complex in¬‚uence of corticosterone on CRH neurons in the
paraventricular nucleus. (b) The relationship between CRH mRNA levels in the
paraventricular nucleus and circulating corticosterone in adrenalectomized (ADX) male
rats with various doses of exogenously applied corticosterone. Note that CRH mRNA is

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