Week 8 (stress) physiology Flashcards
(71 cards)
1
Q
Where is ADH produced?
A
hypothalamus
2
Q
Where is ADH released?
A
posterior pituitary
3
Q
origin difference between anterior and posterior pituitary
A
- posterior pituitary develops from a downgrowth of the hypothalamus called the infundibulum. The neurons of the hypothalamus extend their axons down into the posterior pituitary
- anterior pituitary is derived from another
4
Q
What hormones does the anterior pituitary gland release?
A
- growth hormone
- gonadotropins (FSH, LH)
- prolactin
- ACTH (–cortisol)
- Thyroid stimulating hormone/ TSH (–T3, T4 hormones)
5
Q
removal of pituitary and replacement.
A
- replace at ectopic site - no reversal
- replace under hypothalamus —> blood vessels grow back to connect to hypothalamus and have connection to hypothalamic factors.
6
Q
parvocellular AVP neurons’ role
A
- releases ADH in the hypothalamus and affects the anterior pituitary.
- these neurons send projections to the median eminence.
- AVP/ADH and CRH all regulate ACTH release.
7
Q
CRH stimulation of ACTH release
A
- acts specifically on tissues with CRH receptor.
- through adenylyl cyclase, ATP converts to cAMP and activates PKA
- PKA will stimulate ACTH production and
- secretion.
8
Q
type of CRH receptor
A
GPCR
9
Q
ACTH secretion
A
PKA stimulates Ca2+ influx and release of ACTH from vesicles
10
Q
how does ADH affect ACTH
A
(IP3 and DAG) acting through PKC, it will increase the production of ACTH
11
Q
ADH vs CRH effect on ACTH secretion
A
CRH plays the main role of ACTH secretion
13
Q
ACTH’s receptor
A
(GPCR) MC2 Receptor - specifically on adrenal glands
14
Q
ACTH effect on Cortisol levels
A
- Through MC2R - PKA is activated
- PKA changes gene expression to increase Cortisol production.
15
Q
Adrenal gland cholesterol source
A
- a minor portion is from adrenal synthesis using acetate
- the majority of the cholesterol usage comes from LDL in circulation - dietary.
16
Q
What (production or secretion) determines the cortisol level
A
As a steroid hormone cortisol cannot be stored in vesicles.
17
Q
what does StAR do?
A
it is a regulatory enzyme/protein that controls how much cholesterol gets in the cell’s mitochondria.
The enzyme promotes the transportation of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM)
18
Q
cytochrome p450 enzymes
A
Cytochrome P450s are a group of oxidative enzymes and Six P450 enzymes participate in steroidogenesis
19
Q
P450SCC does…
A
first step of cholesterol processing, catalyzes breakage of the bond between positions 20 and 22 in the cholesterol side chain
20
Q
what are the 2 rate-limiting enzymes for cortisol production?
A
P450SCC (cleavage enzyme)
StAR (regulatory protein)
21
Q
Cortisol acts through…
A
- through cortisol receptors to modify gene expression (relatively slower)
- GR also has non-genomic actions (rapid)
22
Q
non-genomic actions of cortisol
A
- fast acting through kinases including PI3K, MAPK, and AKT.
For example: CORT-activated GR can regulate gap junction and faciliate intercellular communication through MAPK-dependent connexin phosphorylation. - negative feedback to the pituitary and hypothalamus
23
Q
selectivity of genomic vs nongenomic CORT pathway
A
therapeutic benefits might be derived from selectively targeting GR-dependent genomic or non-genomic pathways
24
Q
cortisol effects
A
Response to stress:
1. nutrition metabolism - mobilise glucose (plasma)
2. increase appetite
3. anti-inflammatory effects - expected to be injured in stress.
including: reduces immune response.
25
cortisol as a drug and side effects
due to its **anti-inflammatory and immunosuppressive** actions, glucocorticoid is a widely prescribed drug.
excessive and prolonged usage lead to many side effects including **disrupted metabolism and osteoporosis**.
26
selective glucocorticoid receptor agonists (**SEGRAs**)
Novel potential: which could **keep the negative regulation** of some pro-inflammatory gene expressions, but
**get rid of positive feedback pathways** that may lead to cortisol resistance or other negative effects.
27
**ACTH** and **cortisol** rhythm throughout 24 hrs
1. low during the **night**, starting to get high **before waking up** - mobilise glucose.
2. high during the **day**
28
cortisol in circulation
most are bound to **cortisol binding globulin** ready for **local** action of tissues.
29
plasma cortisol pattern
pulsatile
30
constant CRH effect on ACTH compared to pulsatile
**ACTH** and **Cortisol** are still released in **pulses**.
But the magnitude is **smaller**.
31
Why is **ACTH release pulsatile** even when **CRH is released in a constant rate**
- ACTH-induced gene expression in the adrenal gland is **slow**
- but cortisol released can **rapidly feedback** to pituitary through non-genomic actions.
This **DELAY** leads to **pulsatile ACTH**.
32
delayed feedback from CORT in stress
**Fast feedback mechanisms, such as the binding of glucocorticoids to their receptors, initiate rapid responses like the release of endocannabinoids**, which quickly dampen the HPA axis activity.
This **rapid regulation is complemented by slower, genomic actions** that involve changes in gene expression, providing long-term adjustments to the stress response.
33
What experiment shows that pulsatile ACTH is necessary? (mice)
**Inhibition** of pituitary **release of ACTH** in mice - **exogenous glucocorticoid**.
Only **pulsatile ACTH** can efficiently stimulate the **release of corticosterone**.
34
What **abnormality** will **constant ACTH** lead to in terms of CORT production?
**If ACTH was released in a constant rate**...
gene expression of key enzymes in the adrenal gland will be reduced drastically
for example:
- StAR
- P450SCC
35
Pulsatile CORT effect on behaviour
With pulsatile CORT, the brain performs better in distinguishing emotions on people's faces.
- processing emotions.
36
what commonly leads to Addison's disease?
Tuberculosis
- Induces autoimmune attack on the adrenal gland that leads to adrenal gland hyposecretion - low cortisol
37
pigmentation in addison disease patients
Increased ACTH that leads to stimulation of MC1 receptors on the skin. (melanocortin receptors)
38
What conditions lead to adrenal gland **hyposecretion**?
Addison's disease
congenital adrenal hyperplasia
39
congenital adrenal hyperplasia effect on enzymes
**Loss of steroidogenic enzymes**: lack of steroid hormone synthesis
Leads to deficiency in other enzymes like StAR and CYP11B1:
- cholesterol is not converted to CORT
- lack of cortisol synthesis
40
congenital adrenal hyperplasia other apparent symptoms?
the **accumulation of cholesterol or other CORT precursors** lead to **abnormal androgen production**.
ambiguous genitalia
41
Cushing's disease
a pituitary adenoma – a benign tumor in the pituitary gland.
42
drug use that leads to sustained high cortisol
In **chronic arthritis**:
excess/prolonged **steroid** therapy
43
Cushing's syndrome and protein
Increased **protein catabolism** and reduced **protein production**.
44
**Protein loss** in **Cushing's** leads to
Muscle atrophy
45
cushings and osteoporosis
Increased bone resorption, decreased calcium retention in the body.
46
physiological definition of stress
Any condition that:
- **alters**
- potentially alter
body's **normal homeostasis**.
47
Various modalities of stress:
1. Psychological
2. metabolic
3. physical
48
metabolic stress
metabolic imbalance
49
physical stress
1. pain
2. blood loss
3. movement restriction
50
what releases ACTH in the anterior pituitary
corticotroph cells
51
Chronic stress adaption..
Cortisol release affects the limbic system that +/-vely feedback to stressors.
- Commonly, high CORT has **-ve feedback to stressors from the limbic system**
- will reduce response from stressors
- **ADAPT** to stressors.
52
limbic system in stress response
1. **hippocampus** (a role in memory) Excessive cortisol can damage neurons in the hippocampus, impairing memory and learning. It can also cause the hippocampus to shrink will reduce HPA axis activation,
2. **amygdala** may enhance CORT secretion, during chronic stress, the amygdala's hyperactivity **results from a reduction in inhibitory control** due to altered GABAergic function, stimulate AVP neurons.
53
chronic stress consequences
sustained HIGH level of cortisol:
same effects as Cushing's syndrome
1. cardiovascular diseases
2. muscle atrophy
3. anxiety
4. **cognitive decline - memory**
54
high CORT and depression
**High cortisol** means **worse remission** rate for depression.
55
chronic stress - prolonged high CORT and feedback
**LOSS of CORT -ve feedback** - raises **setpoint** for **HPA axis** and **cortisol**, observed in the nocturnal dip.
1. sustained high CORT
2. **desensitises glucocorticoid receptors** in the brain
3. less -ve feedback of CORT to the HPA axis
4. overactive HPA axis
56
rat exposure to cat (HPA axis)
**Hypothalamus** plays the essential role in responding to chronic stress.
1. increased CORT and ACTH
2. decreased CORT and ACTH after habituation
3. **constant increase of CRH** (even during **habituation**)
57
protein levels in median eminence during stress.
**Reduced** CRH in median eminence
- Reduction due to **secretion**, they are all gone.
58
hypothalamic response to chronic stress (ways to increase hormone)
1. Hypothalamus **releasing more CRH**
2. CRH neurons are **more excitable** and **increased in size**
59
vasopressin in chronic stress
Vasopressin is released synergistically to CRH release.
- **colocalization** at **CRH neurons**
- production by **vasopressin neurons**
Boosting the HPA axis.
60
(CORT receptor) GR levels in chronic stress
Reduced compared to control, LESS negative feedback.
**The response of target tissues** to cortisol may be of **greater significance than the actual levels of the hormone** itself.
61
sustained high CRH - chronic stress effect on pituitary - CRH receptor and binding
More **sensitivity** and **higher baseline ACTH**
1. **increased CRH receptor** due to higher CRH drive.
2. decreased CRH binding - **a reflection of sustained high CRH** in which the receptors are internalised due to activation.
62
why do CRH receptors increase in number in chronic stress
1. higher CRH ---> **drives** to more CRH receptors
2. Pituitary **has less negative feedback** from CORT due to sustained high CORT.
63
chronic activation of CRH receptor at the pituitary leads to..
decreased CRH binding - constant internalisation of receptor - less membrane bound
64
**pretreatment of CORT** effect on pituitary stimulation experiment (rat model)
A rat **pretreated with cortisol** shows less pituitary gland stimulation -- **lower ACTH peak**.
65
chronic stress vs control's effect on anterior pituitary
chronic stress makes the pituitary **more sensitive**:
- **a CRH dose** can make the anterior pituitary **produce more ACTH** than normal.
66
adrenal gland activation period after ACTH stimulation
After ACTH stimulation of adrenal gland, the **adrenal gland STAYS ON for a while**, cannot be suppressed despite low ACTH after.
67
chronic stress effect on adrenal gland
adrenal gland has more response to ACTH now.
**HIGHER cort levels and peaks** from stimulation.
68
what sort of stress could there be?
1. early life stress
2. PTSD
69
early life stress
in utero - or - early post-natal
70
How to show that pre-natal stress actually pre-natal
cross fostering - give them to a non-stressed mother
71
can pre-natal stress be reversed?
Yes. By increased maternal care
