Linda Suryakusuma

Departemen Neurologi FK-UAJ

2015
 A state of real or perceived threat to
homeostasis
 Activates a complex range of responses
involving the endocrine, nervous, and
immune systems  the stress response
 Results in physiological and behavioral
changes that improve chance of survival
 Physiological adaptations include increased
cardiovascular tone, respiratory rate and
metabolism, along with inhibition of
vegetative functions such as feeding,
digestion, growth, reproduction and
immunity
 Behavioral adaptations include increased
awareness, improved cognition, euphoria and
enhanced analgesia
 This complex response is regulated by a
number of neuronal and endocrine systems
 Located in both the CNS and peripheral
tissues
 Principal effector: HPA axis
- Paraventricular nucleus (PVN) of the
hypothalamus
- The anterior lobe of the pituitary gland
- The adrenal gland
- PVN of the hypothalamus syntesize CRF and AVP
- In response to stress, CRF is released into
hypophysial portal vessels that access the
anterior pituitary gland
- CRF binding to its’ receptor on pituitary (CRFR1)
activates cAMP pathway that induce the release of
ACTH into systemic circulation
- In the presence of CRF, AVP elicits synergistic
effects on ACTH release that are mediated
through the vasopressin V1b receptor
- Circulating ACTH binds to the melanocortin
type2 receptor (MC2R) in the adrenal cortex
where it stimulates glucocorticoid synthesis and
secretion into the systemic circulation
 Glucocorticoid regulates physiological events
and inhibit further HPA axis activation
through intracellular receptors that are widely
distributed throughout the brain and
peripheral tissues: IP3 (inositol triphosphate)
and DAG (diacylglycerol)
 The biological effects of glucocorticoids are
usually adaptive; however, inadequate or
excessive activation of the HPA axis may
contribute to the development of pathologies
 Brain
Stress
Stem
Stressor
(e.g.
or
LC)

PVN
 Is the primary regulator of ACTH release from
the anterior pituitary
 Regulates autonomic nervous system,
learning and memory, feeding, and
reproduction related behaviors
 Is widely expressed in CNS (CRFR1) and
several peripheral tissues (CRFR2: adrenal
gland, testis, placenta, GIT, thymus and skin)
 In mice, CRFR1 deficiency cause decreased
anxiety while CRFR2 deficiency cause
increased anxiety
 In the PVN, SON, and suprachiasmatic nuclei
of the hypothalamus
 Magnocellular neurons of the PVN and SON
projections to the posterior lobe of the
pituitary releases AVP directly into systemic
circulation to regulate osmotic homeostasis
 Parvocellular neurons of the PVN synthesize
and release AVP into the portal circulation,
where it potentiates the effects of CRF on
ACTH release from the anterior pituitary
 AVP in PVN is increased in chronic stress 
supports the hypothesis that AVP maintains
ACTH responsiveness to novel stressors
during periods of chronic stress
 In response to CRF, ACTH is released from
pituitary into systemic circulation where it
binds to specific receptor (MC2R) in the
adrenal cortex
 Activation of MC2R stimulates
steroidogenesis and the secretion of
glucocorticoids, mineralocorticoids and
androgenic steroids
 Glucocorticoids (cortisol), in turn, regulates
metabolic, cardiovascular, immune and
behavioral processess
 The HPA axis is subject to feedback inhibition
from circulating glucocorticoids
(glucocorticoid negative feedback)
 Mineralocorticoid Receptors (MR) regulate
basal HPA tone
 Glucocorticoid Receptors (GR) regulate
negative feedback following stress  in PVN
and hippocampus
 Neurons in the PVN are innervated by afferent
projections from multiple brain regions (brain
stem neurons, lamina terminalis, extra-PVN
hypothalamic nuclei, and forebrain limbic
structures)
 These cell groups integrate and relay
information regarding a wide array of sensory
modalities to influence CRF expression and
release from PVN
 Depression resulted from an interaction between
environmental stress and genetic/ developmental
predisposition
 The set point of HPA-axis activity is programmed
by genotype, but it can becchanged by
developmental influences and early negative life
events
 Long lasting hyper(re)activity of the CRF neurons,
resulting in increased stress responsiveness and
reflecting a glucocorticoid resistant state, is
common in depressed individuals
 Almost all environmental and genetic risk
factors for depression appear to correlate
with increased HPA-axis activity
 On the other hand, when patients or animals
are treated with antidepressants,
electroconvulsive therapy, or showed
spontaneous remission, the HPA-axis
function returns to normal
 Changes in the brain centres that control the
stress reponse, such as the hypothalamus,
have also been reported
 In the PVN of patients with major depression,
vasopressin and oxytocin neurons are
activated as well, which may have functional
consequences for HPA-axis reactivity, since
vasopressin potentiates the effects of CRF
 Activation of oxytocin in depression has been
connected to eating disorders seen in
depression
 Patients with depression have altered
serotonin (5HT), noradrenaline and dopamine
production by the brain
 Impulsive aggression and suicidal behavior
have been related to a decreased serotonergic
activity
 On the other hand, noradrenaline is increased
in the hypothalamus of depressed patients
 Patients with major depression show a much
stronger CRF neuron activation, i.e: a four-
fold increase in total number of CRF
expressing cells, increased CRF neurons with
vasopressin colocalization and increased
CRF-mRNA in the PVN
 These abnormalities are, in part, normalized
after pharmacotherapy
 Normalization of the HPA-axis decreases
relapse probability
 The HPA system is activated in depression
and affects mood, via CRF and cortisol
 In depressed patients, stress acting on HPA
results in a disproportionately high activity of
the HPA system because of a deficient
cortisol feedback effect due to the presence
of glucocorticoid resistance
 This glucocorticoid resistance may either be
caused by a polymorphism of corticosteroid
receptor or by a developmental disorder
 In depressed patients, AVP neurons in the
SCN also react to the increased cortisol levels
and subsequently fail to inhibit sufficiently
the CRF neurons in the PVN
 Such impaired negative feedback mechanism
may lead to a further increase in the activity
of the HPA system in depression
 Both high CRF and cortisol levels contribute
to the symptoms of depression
 Anti depressants inhibit the activity of CRF
neurons in the PVN
 The increased drive of the HPA-axis in
depressed patients is mediated either by CRF,
by vasopressin, or by both
 Thereby, CRF receptor antagonists, cortisol
synthesis inhibitors, or corticosteroid
receptor antagonists may be effective in
depressed patients
 Women have a significantly higher
glucocorticoid and mineralocorticoid receptor
mRNA expression than men in the temporal
lobe and prefrontal cortex  women are
more at risk than men for major depression
 Overexposure to glucocorticoids during
chronic stress damages the brain, particularly
affecting the hippocampus, thereby seriously
compromise memory function and cognition
 Furthermore, damage to the hippocampus
was proposed to cause a disinhibition of the
glucocorticoid negative feedback, which
would lead to a further activation of the HPA-
axis, to subsequent rises in glucocorticoid
levels and thus to accumulating damage to
the hippocampus
 There is a close functional interaction between
the HPA-axis and the HPG-axis
 For example: estrogen stimulates HPA-axis
 Pregnant women as well as women receiving
high-dose estrogen therapy have elevated levels
of free cortisol, while estradiol can downregulate
glucocorticoid receptors in the anterior pituitary,
hypothalamus and hippocampus
 This, in turn, will interfere with glucocorticoid
negative feedback and will consequently increase
the activity of the HPA-axis
 Variations in the sex hormone levels during a
woman’s reproductive years are bound to
affect the stress system
 The prevalence of major depression increases
during the reproductive years, especially
during times when sex hormone levels show
rapid fluctuations, such as in the
premenstrual, antepartum and postpartum
periods, and during the transition phase to
the menopause
 The change of reproductive hormones is
speculated to play a more important role than
the absolute level of the sex hormones in the
etiology of depression
 During the reproductive years, a woman is
exposed to a monthly fluctuations of circulating
estradiol that may affect her behavior
 Premenstrual syndrome is characterized by
depression, anxiety and mood swings during the
last week of the luteal phase, with the decrease
of plasma estradiol levels
 Other studies have suggested that the period of
peak estradiol secretion immediately before
ovulation is associated with elevations in mood, a
phenomenon that might contribute to fecundity
 In contrast to women, depressed men
generally show decreased testosterone levels
 Studies in anabolic androgenic steroid users
show that some of them develop manic or
aggressive reactions
 Maintenance of homeostasis requires activation
of a complex range of responses involving the
endocrine, nervous, and immune systems,
collectively known as the stress response
 The final common pathway of the stress response
is the HPA-axis
 There is a close functional interaction between
the HPA-axis and the HPG-axis
 The understanding of HPA-axis and HPG-axis
physiology forms the basis of pharmacotherapy
for psychiatric and behavior disorders