ANAT 322 Lecture Notes - Lecture 13: Binge Eating, Aromatase, Rodent
7 Jun 2018
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ANAT 322 Winter 2017
Lectures
Lecture 13:
→ The Hypothalamus Pituitary Adrenal (HPA) Axis and the Stress Response
2. The concept of stress was invented by Hans Selye who worked in the anatomy department at McGill
Uiersity. The first papers that set up the oept of stress ere ritte y hi i the 93’s.
He was the first one to look at rats while exposing them to stressors and he noticed that the animals
developed gastric ulcers and had involution of the thymus, responsible for the maturation of immune
cells, and enlargement of the adrenal glands. He called it stress or general adaptation syndrome which is
constituted of three stages. The alarm reaction is the acute response to stress, the resistance phase in
which the organism is trying to cope with the stressor and the exhaustion phase which nowadays is
called allostatic load in which the organism is not capable anymore of appropriately responding to the
situation.
3. Since then, a lot of people has been trying to define what stress is and the concept that can be put
around that along with the physiological changes.
4. If we look at the physiological response to the stressor, there are two arms to the response.
The neuroendocrine response involves the inputs of the stress signals to neurons in the
paraventricular nucleus of the hypothalamus (PVN) containing CRH or CRF which is present in
parvocellular cells. Upon stress stimulation different inputs converge to those neurons which will release
CRF at the median eminence that are transported to the anterior pituitary which has CRF receptors on
corticotropic cells that produce POMC that is cleaved into ACTH and travel in the general circulation to
affect the cortex of the adrenal glands which releases glucocorticoids that are the end target hormones
affecting the activity of the axis through an inhibitory feedback system (classical loop). This is a slow
response to stress.
The sympathetic nervous system is also activated which allows a quick response to the stressor. If we
encounter a stressor, the heart rate goes up, the blood pressure goes up, we send oxygens to different
tissues, muscles increase their activity if we need to move, and all of these are achieved through the
production of epinephrine and norepinephrine. This is a faster response to stress.
5. The sympathetic nervous system also affects the adrenal glands but at the level of the medulla where
epinephrine and norepinephrine are released (catecholamines).
Both glucocorticoids and catecholamines are responsible for the increase in cardiovascular tone,
blood pressure, mobilization of stored energy to muscle for a behavioral response, transient
enhancement of immunity in case we have an immune challenge such as a pathogen or virus, and
inhibition of costly, long-term processes such as growth and reproduction. Inhibition of growth has been
seen in infants that has been kept in orphanages and this is called stunted growth or psychological
dwarfism due to stress or deprivation conditions. In females, reproduction can stop during stress
because the menstrual cycle can stops and there is reduced fertility.
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ANAT 322 Winter 2017
Lectures
In the acute response, we try to respond to the needs of the brain such as oxygen or energy. We
acutely inhibit gastric emptying.
6. There are a number of different inputs to the PVN and some are direct and some indirect.
In terms of the indirect inputs, the important ones are from the amygdala which is important in
emotional processing and fear, the ventral subiculum, prefrontal cortex and cortex which are important
for the cognitive function, associative function and detection of what stress means and the lateral septal
complex. These are indirect in that they project to the bed nucleus of the stria terminalis and then they
project to the PVN. Other hypothalamic regions also send indirect projections to the PVN like the
ventromedial hypothalamus.
There are also direct projections from hypothalamic subnuclei that affect the PVN and they come
from dorsomedial hypothalamus, the arcuate nucleus important for food intake and received metabolic
information from the periphery, the lateral hypothalamic area important for food intake, attention,
activity and arousal. Direct projections are coming from the brainstem and the medulla to the PVN.
PVN sees direct information form the periphery coming from the brainstem area so if we have pain,
hemorrhage, sensory stressors or others will be send directly to the PVN. If we have emotional stressors
involving the amygdala or prefrontal cortex, these will be indirect projections to PVN neurons.
7. CRF is a short peptide of 41 amino acids produced from a larger precursor molecule called pre-pro-
CRF and has a signal peptide and a single active peptide and a short portion that is not active so cleavage
of this inactive portion leads to CRF. It was discovered in 1991 so it is relatively recent.
There is about 80% homology between human CRF and ovine CRF whereas the rat CRF is different.
There are other CRF-like molecules such as urocortin in amphibians, sauvagine in frog and urotensin in
fish.
8. CRF is abundant in the parvocellular neurons of the PVN. Colchicine treated animals have blocked
axon transport so we can visualize the CRF in the neurons in the PVN.
In C, after adrenalectomy or removal of the adrenals, there is large increase in production in the
parvocellular neurons and even the fibers coming out have CRF in them.
9. When we look at the response of parvocellular neurons to stressor, we can identify the expression of
CRF mRNA or CRF heteronuclear RNA (hnRNA).
On the top panel, we can see the species of RNA that goes up really fast after a stressor and comes
down quickly so it is a very transient signal. mRNA goes up with a longer time frame and stays there
longer after the onset of stressor.
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ANAT 322 Winter 2017
Lectures
On panel B, we can see that hnRNA goes up within the first half hour and the signal goes down
quickly. This is a rapid and transient induction of CRF in the parvocellular neurons followed by an
accumulation of mRNA in those neurons.
10. CRF neurons and fibers run laterally/ventrally and end in the portal capillaries of the median
eminence.
11. Upon activation of CRF, there are two types of receptors that can be activated which are CRF-1
receptors and CRF-2 receptors that are both G protein transmembrane receptors.
If we look at the specificity of the receptor ligand, we have a number of CRF-1 receptor ligands that
have a domain that is in the large extracellular part of the molecule whereas the CRF-2 receptor ligand
have two domains that are closer to the membrane on the extracellular part.
12. The activation of CRF receptors leads to a number of different intracellular signaling cascades.
In particular, once you have the activation of the CRF receptor, you can activate Gs subunits which
leads to the activation of the adenylate cyclase (AC), production of cyclic AMP which activates PKA,
leading to phosphorylation of CREB ad gene transcription through this pathway (left side of picture).
You can also activate Gq subunits leading to activation of phospholipase C (PLC) which produces
insoluble phosphates (diglyceride or diacylglycerol or DAG) leading to activation of PKC and gene
transcription (right side of picture).
Upon activation, some of the receptors are desensitized and downregulation of receptors occur so
that we internalize through endosomes and the receptors are recycled or through lysosomes the
receptors degrade.
Most of the binding to CRF type I receptor primarily leads to activation of PKA pathways and cAMP
production.
13. After the discovery of CRF, people have discovered that there are other proteins called urocortins
that also bind to the CRF receptors but have different affinity for these. If we look at the native protein,
CRF binds to CRF type I and II receptors.
The urocortin has three molecules and UCN1 binds to both receptors, UCN2 binds exclusively to CRF
type II and UCN3 will also exclusively bind to CRF type II. These ligands have been useful to differentiate
the effects of CRF on both type I and type II receptors because we can selectively use these.
The affinity or the binding of CRF to type II is lower than to the type I since this is the primary
receptor found in the pituitary and many regions in the brain.
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Document Summary
The hypothalamus pituitary adrenal (hpa) axis and the stress response: the concept of stress was invented by hans selye who worked in the anatomy department at mcgill. The first papers that set up the (cid:272)o(cid:374)(cid:272)ept of stress (cid:449)ere (cid:449)ritte(cid:374) (cid:271)y hi(cid:373) i(cid:374) the (cid:1005)93(cid:1004)"s. He called it stress or general adaptation syndrome which is constituted of three stages. The neuroendocrine response involves the inputs of the stress signals to neurons in the paraventricular nucleus of the hypothalamus (pvn) containing crh or crf which is present in parvocellular cells. Upon stress stimulation different inputs converge to those neurons which will release. The sympathetic nervous system is also activated which allows a quick response to the stressor. This is a faster response to stress: the sympathetic nervous system also affects the adrenal glands but at the level of the medulla where epinephrine and norepinephrine are released (catecholamines).
