Second year undergraduate essay written for the Cell Pathology module of the Biomedical Sciences course at the University of Oxford.
//Essay title: Discuss the mechanisms involved in chronic stress response. How are these mechanisms controlled?//
Very helpful for tutorial preparation and exa...
Discuss the mechanisms involved in chronic stress response. How are these
mechanisms controlled?
Survival depends on the maintenance of homeostasis in face of constant challenges by
various internal or external adverse forces known as stressors, stressors cause stress when
homeostasis is disrupted or is perceived to be so. As recognized by Selye over 80 years ago,
sufficiently high level of stress can trigger a response called general adaptive syndrome
(GAS), regardless of the nature of the stressful stimuli. In this essay, we describe effector
mechanisms of GAS and how they are controlled, focusing on the hypothalamus-pituitary-
adrenal (HPA) axis that is activated by chronic stress.
GAS is a three-stage response to stress, its regulation is vital because various diseases are
associated with its inappropriate or prolonged activation. Stress can have various origins,
physical or psychological, and stressors can be acute or chronic. Acute stressors such as
exercise and blood loss are often transient, whereas chronic stressors like infection or
emotional problems elicit a prolonged state of stress. GAS begins with an alarm reaction
stage, commonly known as the fight-or-flight response which prepares the body for
challenges through activation of the sympathetic nervous system. If stress persists, the
resistance stage kicks in where sustained stress response depend largely on the HPA axis
which produces stress hormones (cortisol and adrenaline). The elevated cortisol level
represents an attempt to keep up with the stress-induced physiological changes by
mobilising body’s resources Finally, chronic stress may lead to exhaustion where the body’s
resources have been depleted due to failure of adaptation.
The SNS is instantaneously activated in stress, physically preparing the body to act against
stressors. SNS originating in the spinal cord innervates virtually all organs, including
chromaffin cells of the adrenal medulla which secrete catecholamines when stimulated by
stress. Adrenaline produced enters the circulation to supplement and prolong the effect of
direct noradrenergic SNS stimulation of organs. To illustrate, SNS has widespread functions:
increasing ventilation to meet raised metabolic hence oxygen demand; increasing cardiac
output to speed up delivery of oxygen, nutrients and blood-bourne substances like
hormones; Redirection of blood flow to increase perfusion to the aroused brain, heart and
muscles. Moreover, fuel availability is increased by the actions of adrenaline and hormone-
sensitive lipases during stress.
Since effects of SNS in stress is transient, the central component of chronic stress response
is the HPA axis. The HPA axis begins in the hypothalamus where the 41-amino-acid
neuropeptide corticotrophin releasing hormone (CRH) released from parvocellular neurons
(PVN) enters the hypophyseal portal blood vessels to the anterior pituitary gland, where it
acts via a Gαs-coupled type 1 CRH receptor to trigger release of adrenocorticotrophic
hormone (ACTH) from corticotrophs. In addition, arginine vasopressin (AVP) works
synergistically with CRH to stimulate ACTH secretion although it is not a potent
secretagogue alone. The effect of stress on the biosynthesis of CRH and AVP was studied by
Herman et al. (1995), the group mimicked chronic stress on mice with a chronic variable
stressor (CVS) paradigm and results showed a 61% and 16% increase in amount of CRH and
AVP mRNA in the PVN respectively. This upregulation is consistent with enhanced HPA
activity and indicates the crucial role of CRH in maintaining HPA upregulation in face of
prolonged stress. The CVS paradigm mimics stress by introducing unpredictable stressors (eg
, restraint, hot air stream, shaking etc.) over a period of time, and a caveat of this protocol is
the difficulty to quantitatively fix the implemented stress leading to difficulties in
reproducing the findings. Also, extra care is needed when transferring findings from mice to
humans owing to their extensive physiological differences and the fact that they face very
different stressors in lives. Circulating ACTH is the key regulator of glucocorticoid secretion,
they act on type 2 melanocortin receptors on adrenal cortex cells to initiate synthesis of
glucocorticoids from cholesterol. The major type of glucocorticoid in human is cortisol,
which can be interconverted with its inactive metabolite cortisone by the action of 11β-
hydroxysteroid dehydrogenases, inactivation of cortisol by this enzyme is important in its
clearance from the body. Since the adrenal gland is an essential stress response organ that
is a part of both the HPA axis and the symptho-adrenomedullary system, chronic stress
exposure is expected to cause hyperplasia and hypertrophy, thereby increasing maximal
cortisol response to ACTH. A study led by Herman et al. (2006) confirmed this by
demonstrating enhanced adrenal function, indicated by greater weight and nucleic acid
content, following a 14-day CVS paradigm where exogenous ACTH is administered to rats
pre-treated with dexamethasone to block endogenous ACTH release.
Cortisol controls homeostasis and enable us to cope with stress by altering expression of
approximately 10% of our genes. Cortisol synthesized in the adrenal cortex diffuses into the
plasma, where around 90% of it is bound to corticosteroid-binding globulin (CBG,
transcortin). Only the small amount of free cortisol is able to enter target cells and act via
two types of intracellular nuclear receptors – glucocorticoid receptor (GR) and
mineralcorticoid receptor (MR). Unbound cytoplasmic GR is complexed to a chaperone
protein (i.e. the heat shock protein hsp90), which dissociates upon cortisol binding so that
the cortisol-GR complex can translocate to the nucleus. Activated GR controls transcription
in two ways, it can function as homodimers acting as transcription factors (TFs) by
associating with glucocorticoid response elements (GREs) of target genes to alter their
expression. Otherwise, activated GR can indirectly modulate transcription through protein-
protein interaction with other TFs. Experiments in cultured cells where effects of point
mutations in GR were studied showed that GR is capable of inhibiting TFs such as NF-kB and
AP-1 without requiring dimerisation or DNA-binding. As its name suggests, the major action
of glucocorticoids like cortisol is to increase plasma glucose concentration through its action
on liver, fat and muscles, this is especially important for the brain as it only utilizes glucose
as fuel. During stress, cortisol enhances gluconeogenesis in the liver to generate glucose
from non-carbohydrate carbon substrates, these substrates are in turn produced from lipid
and protein catabolism in liver and peripheral tissues which are accelerated by cortisol.
Cortisol has numerous actions other than their effect on glucose-regulatory tissues, for
example, it is an important regulator of immune and inflammatory processes by interfering
levels of leukocytes and inflammatory mediators. By dampening inflammation, cortisol
prevents it from being disruptive as seen in chronic inflammatory diseases, but its
immunosuppressive properties can render the body more susceptible to infections under
stress. Other effects of cortisol include increased cardiac output, raised blood pressure,
altered calcium and bone metabolism. In addition, cortisol has central effects on the brain
such as worsening memory and modifying emotions when acting on the hippocampus.
Further, cortisol acts on the hypothalamus to increase thyrotrophin releasing hormone
(TRH) that lead to thyroid hormones production which in turn increases metabolic rate,
whereas reducing gonadotrophin releasing hormone (GnRH) secretion prevents further
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller BiomedAtOxford. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $16.95. You're not tied to anything after your purchase.
