ANAT 322 Lecture 15: ANAT 322 - Lecture 15
7 Jun 2018
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ANAT 322 Winter 2017
Lectures
Lecture 15:
→ Chronic Stress and Disease
2. There is a number of changes in many different systems between an acute stressor and a long-term
exposure to stress.
The immune system under acute conditions, some of the anti-inflammatory cytokines are secreted to
protect the organism from potentially harmful inflammation. On the long term, there is desensitization
of some of the system and in particular we can see cases of immunosuppression and increase
vulnerability to infection.
In terms of metabolism, in an acute situation you want to mobilize energy stores and react to the
stressor to mount an adequate response so you will increase glucose and fatty acids. Then you will
restore the stores that have been used so you increase the mobilization of energy stores. In long term
we see the development of the metabolic syndrome with elevated levels of glucocorticoids, insulin
resistance, diabetes, obesity and cardiovascular disease.
In the central nervous system, the acute or immediate reaction to stress will improve cognitive
function in order for the person to run and have the most adequate behavioral response. In the chronic
stress condition, you have neurodegeneration, impaired mood and cognitive function.
The cardiovascular system is also affected which is part of the metabolic syndrome to develop
hypertension in chronic stress conditions.
Reproductive function is also affected and very often you will see irregularities in the menstrual cycle
and sometimes in severe cases you can see total amenorrhea. This is also seen with marathon runners
because of the stress imposed in the body as well as with ballet dancers that often show stop in
menstruation. It is not seen in swimmers so there is a difference even though the effort is intense as
well.
In terms of gastrointestinal tract, animals under intense stress develop gastric ulcers which is the
same in humans under chronic stress conditions and not necessarily under acute stress.
3. In the graph we can see basal cortisol secretion under chronic stress conditions in humans and we can
see the increase in cortisol levels when we wake up and it goes down when we go to bed.
Under mild stress conditions we start to see a bit of an increase in cortisol levels in the trough. As we
increase to moderate stress conditions, we start to see increases in cortisol at the initial peak and at the
trough. With very strong stressors, throughout the day we have very high levels of glucocorticoids and
this is under very severe conditions but most of the time we are at the moderate stress.
We do not need to have a huge increase in levels of glucocorticoids to be in a situation of chronic
stress. The most sensitive time to measure the effects of chronic stress is when the levels of
glucocorticoids are down because under chronic stress conditions you will see the elevations.
4. How do we see a dysregulation of the HPA axis under chronic stress?
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ANAT 322 Winter 2017
Lectures
Under acute stress, we see a rapid increase in ACTH that falls rapidly and an increase in
glucocorticoids (corticosterone in this case) that peak later than ACTH and comes down slowly. The
increase in glucocorticoids is important to turn down the ACTH response.
In rodents, we can either expose the animal to a repeated stressor day after day for about a week.
Under those conditions we will see a homotypic stressor because the same stressor is used every day
and there will be habituation of the stress response. Compared to the acute stress, a repeated exposure
for seven days will lead to a smaller response in terms of ACTH and corticosterone and this is what is
called habituation. This is a good thing because you will prevent some of the effects of having always
elevated levels of glucocorticoids. You can challenge the animal with a different stressor after the seven
days and there will be a larger response than the original response so we have sensitize the system to a
novel stressor. When you use a heterotypic stressor regimen you see sensitization which is an indicator
of chronic stress exposure.
5. The adaptation to homotypic stressors is age-dependent and this has consequences on the way we
see the stress response as a function of age.
In graphs A and B, this is an acute stressor and we compare adult animals and prepubertal animals.
When we look at the plasma ACTH curve response, we see a higher ACTH response in prepubertal
animals compared to the adults which is something that has been documented in rats.
In graph C and D, we are looking at chronic stress with a homotypic stressor and what we see is that
the response in terms of ACTH and corticosterone is reduced if we habituate correctly to the stressor.
Prepubertal animals show a larger response which means that they are not capable of adapting to a
repeated stressor.
In conclusion, adolescent animals show a larger response to stress but also an impairment in the
ability to habituate to stress.
6. Under chronic stress conditions there is a tonic increase in glucocorticoids and sensitization to
heterotypic stressors. What happens is that in these situations we start recruiting additional neuronal
structures that will impact CRH neurons under chronic stress conditions.
The paraventricular thalamus that becomes only recruited under conditions of chronic stress. If you
do experiments and look at Fos responses (neuronal activation), you will not see an increase in Fos
under acute stress conditions in an animal but you will start to see a mobilization of the PVthalamus
under chronic stress conditions which means that inputs and output to and from this structures to the
hypothalamus have been increased.
The same with the amygdala, the BNST and the locus coeruleus are regions that become activated
under chronic stress conditions. The locus coeruleus provides noradrenergic innervations to the
prefrontal cortex and that is important in the case of depression where we see that the structure is
overactivated.
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ANAT 322 Winter 2017
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One important aspect of the amygdala which is important for the regulation of emotion and fear
responses is that it can become sensitize under chronic stress conditions. In contrast to the PVN where
CRF turns off the production of CRF, glucocorticoid stimulates the production of CRF.
7. Under chronic stress condition, one can use food intake to reduce the activity of the HPA axis
(comfort food).
In the first graph, we see the response to stress with ACTH and glucocorticoids that turn off the
response to ACTH. If we look at the second graph which shows the relationship between plasma
glucocorticoids and the intake of comfort food, the more glucocorticoids are circulating in the presence
of insulin, the more we see an increase in comfort food. The animal is trying to compensate for the
increase in glucocorticoids by increasing the amount of comfort food. This phenomenon involves a
number of regions but in particular the nucleus accumbens and the ventral tegmental area (VTA) which
are important to mediate reward.
As a function of glucocorticoid increase, you also see an increase in CRF activity in the amygdala
because glucocorticoids have a stimulatory effect on CRF in the amygdala and it increases the general
output of the structure to have effects in many regions such as the PVN. If you look at CRF activity as a
function of abdominal fat, you will see that the large the increase in fat you reduce the CRF activity in
the PVN. The abdominal fat not only leads to production of glucocorticoids through the increase in the
enzyme that can transfer the inactive metabolite to its active state (11-βHSD1) but there is also a factor
in the abdominal fat (maybe leptin) that can turn off CRF in the PVN. The intake of comfort food is
comforting because it has the reward aspect and also serves to turn off the activity of the HPA axis.
8. Allostasis is the process of maintaining the stability by an active means. It is the fact that we do this by
a dynamic mean and tuning on the systems back and forth or up and down and the messengers that you
want are really cortisol, catecholamines and neuropeptides to maintain overall balance.
Allostatic load is when the system is not capable to regulate anymore and it has been subjected to
chronic stress and is trying really hard to maintain allostasis.
Individual differences, environmental stressors, trauma or abuse, major life events can impact how
we perceive stress and the behavioral responses we can have to stress. Physiological responses are
trying to adapt to novel circumstances and it does so to the expense of the allostatic load.
9. Different types of adaptation to chronic stress.
Normal adaptation is when the response goes up and gets turned down in a certain amount of time.
One type of maladaptation is when we are constantly responding to a stressor with no habituation or
adaptation. Another type of response is to increase the response but not being able to turn it down and
we can see this in cases in which we have impairments i gluootioid’s egatie feedak. Aothe
type of maladaptive response is the lack of response overall which is the case we see in PTSD where we
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Document Summary
Chronic stress and disease: there is a number of changes in many different systems between an acute stressor and a long-term exposure to stress. The immune system under acute conditions, some of the anti-inflammatory cytokines are secreted to protect the organism from potentially harmful inflammation. On the long term, there is desensitization of some of the system and in particular we can see cases of immunosuppression and increase vulnerability to infection. In terms of metabolism, in an acute situation you want to mobilize energy stores and react to the stressor to mount an adequate response so you will increase glucose and fatty acids. Then you will restore the stores that have been used so you increase the mobilization of energy stores. In long term we see the development of the metabolic syndrome with elevated levels of glucocorticoids, insulin resistance, diabetes, obesity and cardiovascular disease.
