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HPA axis (finished) Flashcards

1
Q

What makes up the HPA axis?

A

Hypothalamus, Pituitary gland & Adrenal glands

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2
Q

What happens in the HPA axis?

A

1 - Hypothalamus activated by stress

2 - Hypothalamus signals to pituitary gland which releases hormones (CRH)

3 - Anterior pituitary which releases ACTH = signals to Adrenal cortex

4 - Adrenal cortex releases cortisol

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3
Q

What does CRH stand for?

A

Corticotropin releasing hormone

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4
Q

What does ACTH stand for?

A

Adrenocorticotropic hormone

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5
Q

What is the HPA axis like in depressed patients?

A

They have a hyperactivation (about 50%) of the HPA

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6
Q

What kind of loop is the HPA axis and what is this like in depression?

A

HPA = a negative feedback loop
(inc cortisol acts on hypothalamus & anterior pituitary to release less CRH & ACTH)

  • In healthy patients this should inhibit pituitary gland and hypothalamus
    = recovering from stressor
  • In depression- HPA axis is hyperactive (50% increase in signalling route) = negative feedback loop not present
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7
Q

How do depressed patients display HPA hyper-activation?

A
  • ↑ CORTISOL in saliva, plasma & urine
  • ↑ CRH in CSF & in limbic brain region
  • ↑ size (& activity) of pituitary & adrenal glands
  • Impaired -ive feedback = continuously elevates cortisol levels
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8
Q

How does CORT (endogenous glucocorticoid hormone) differ in humans compared to rats, mice, birds & reptiles etc?

A
  • Humans have CORTISOL
  • Other animals have CORTICOSTERONE –> this lacks an OH grp compared to cortisol (only difference)
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9
Q

What does acute stress response do to ACTH & CRH?

A

Increases the levels of them- quite dramatically (8x)

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10
Q

Is the structure of CRH AND ACTH similar?

A

Similar structure- only a few different amino acids dependent on different species

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11
Q

What is the structure of CRH?

A

A 41 amino acid chain

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12
Q

What is the structure of ACTH?

A

A 30 amino acid sequence

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13
Q

Describe the cycle of the 2 peptides CRH and ACTH

A

Changes within the day- 24 hour cycle
Lowest point of the night = low peptides levels

In the day = larger levels of peptides present

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14
Q

What are the half lives of ACTH & CORT?

A

Relatively long:
ACTH / CRH = 19 min

CORT = 49 min

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15
Q

What are the levels of ACTH & CORT during acute stress?

A

ACTH = 40-80 pg/ml

CORT = 20-35 ug/100ml

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16
Q

Where are the adrenal glands located?

A

Above the kidneys

(They are small endocrine glands essential for life)

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17
Q

What are the 5 zones of the adrenal glands called (top to bottom)?

A
  • Capsule (this is just the top of it but I have counted it in the layers

1 - Zona glomerulosa

2 - Zona fasciculata

3 - Zona reticularis

4 - Medulla

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18
Q

What is the largest past of the adrenal glands?

A

The medulla

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19
Q

What is also running through the different zones of the adrenal glands?

A

Capilliaries

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20
Q

What is the role of the 3 zones of the adrenal cortex?

Name them

A

They produce the stress hormones (cortisol or aldosterone)

These are known as steroids

  • Zona glomerulosa
  • Zona fasciculata
  • Zona reticularis
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21
Q

Where are steroids and catecholamines made in the adrenal glands?

A

Steroids = top 3 zones (known as the adrenal cortex)

Catecholamines = medulla

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22
Q

What are the outer and inner compositions of the adrenal glands called?

A

Outer comp = adrenal cortex (top 3 zones)

Inner comp = medulla

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23
Q

What are the two steroids produced by the adrenal cortex & give examples of these?

A

Zona glomerulosa = Glucocorticoids e.g. cortisol

Zona fasciculata = Mineralocorticoid e.g. aldosterone

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24
Q

What does the medulla produce? Give examples

A

Catecholamines

E.g. noradrenaline & adrenaline that are released into blood
(As a consequence of stress activation)

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25
Where are Chromaffin cells found?
In the medulla of the adrenal glands
26
What 2 things are the adrenal glands controlled by?
Dual control by: autonomic & endocrine
27
Describe the endocrine axis of adrenal gland control (other HPA signalling route)
* Mediated by **intermediolateral horn** * Targets **sympathetic nervous system** * Activates **adrenal glands** * In turn produce NTs - **adrenaline** and **noradreanaline**
28
During stress, what happens in the HPA axis?
Increased responses = enhances activities of both pathways
29
Name 3 different forms of stress
Physical Metabolic Psychological
30
Describes the effects of the release of glutocorticoids e.g. cortisol and Mineralocorticoid e.g. aldosterone
- Induce the **release of energy to cells** = increases *gluconeogenesis, lipolysis and proteolysis* - **Immune system** is *suppressed* - **Inflammation** altered - Risk of **depression and anxiety** in long term - Cardiovascular system effects- increases BP
31
Are the effects of cortisol beneficial?
Yes in short term activation but in the long term activation = detrimental negative effects on the body
32
Describes the effects of the release of stress neurotransmitters (adrenaline and noradrenaline)
Increased HR , BP, bronchodilation and blood flow to skeletal muscle = all changes are the basis for a fear response which is either a fight/flight response
33
The HPA axis has changes that occur in stressful events, when do these changes also occur?
Circadian events that are essential for survival
34
What is the trigger for changing the activity of the HPA axis?
Suprachiasmatic nucleus (SCN) as it receives the impulse from light activity
35
What is the SCN?
= central pacemaker of the circadian timing system regulates most circadian rhythms in the body
36
What does the SCN do according to changes in light?
* Overcomes the *hypothalamus-pituitary gland* signalling * Instead **directly activates adrenal gland** in circadian manner * This alters expression of *stress hormones* - adrenaline and NA
37
What gene is important in circadian rhythms and how does it work?
CLOCK gene expression Leads to circadian change of hormones via **SCN activation** directly on adrenal glands bypassing Hypothalmus + pituitary
38
What kind of circadian changes occur throughout the day?
* Inc in BP & HR in the day but during night-time these drop * Plasma levels of cortisol also do this --> peak just after dawn to induce changes described previously (blood pressure, energy metabolism, heart rate etc)
39
Describe and experiment showing the influence of cortisol/corticosterone
In mouse model = * Corticosterone (like cortisol in humans) levels changes in circadian manner- increase during day and decrease during evenings * Mutate CLOCK genes = reduces function = delay onset of increase of corticosterone
40
Is the increase in cortisol/corticosterone consistent- explain this?
No have short term spikes and troughs = episodic bursts essential for signalling in the body- allowing for cells to recover to return to an activity state
41
What happens when you add a stress response to different circadian activities
In night and day- cortisol and stress hormones increased in reponse to a stressor system can work independently in any point of the circadian rhythm
42
How does long-term exposure to stress compare to short term?
* Short term = **fight / flight response (involved slight supression of gut, immune and reproductive function), increased anxiety behaviours, arousal, scanning attention and memory** = changes are required for survival but if changes occur for too long: * Long term exposure to stress = **reduction in gut function, immune function and reproductive function** continued anxiety like behaviours = Anxiety and depression Continued arousal = sleep disturbances Continued scanning attention = attential disruption Continued memory = memory loss (neurodegeneration) Continued energy metabolism = hyperglycaemia increased risk of diabetes Continued cardiovascular effects = cardiovascular disease
43
How do we study the effects of stressors?
Fairly easily: Measure plasma concentration of CORT in response to different stimuli which cause stress to different animals at different degrees
44
Describe a study showing response of mice/rats to different stressors
Remove bedding Put in circular arena elevate area in which the sit Restrain in tubes swimming food shock experiments = all induce a stress response which induces ACTH and corticosterone concentration in plasma
45
What produces Glucocorticoids e.g. cortisol Mineralocorticoid e.g. aldosterone?
medulla in adrenal glands
46
What are the specific receptors in which mineralcorticoids and glutocorticoids act?
MR = mineralcorticoid receptors GR = glutocorticoid receptors
47
Where are GRs and MRs present?
widespread expressed throughout the brain: - high density in hippocampus and hypothalamus and brain stem
48
What does the high density of MRs and GRs related to in each part of the brain?
Hippocampus = relates to learning and memory function Hypothalamus = relates to negative feedback loop of stress hormones Brain stem (predominantly MRs) = related to locus coeruleus (=nucleus) which is directly related to stress response
49
What is the locus coeruleus?
= nucleus located in the brain stem which increases activity in response to stress
50
Where are noradrenergic neurons located in the brain?
Noradrenergic neurons are widespread throughout the brain- so impacts many different circuits (shown in green) **They originate from the Locus corelus**
51
Where do noradrenergic neurons originate?
Predominantly in the locus coeruleus
52
What has the dysfunction of noradrenaline signalling been implicated in?
Alzheimers Ageing related dysfunction and neurodegeneration
53
Compare the locus coeruleus with a healthy control and an Alzheimers patient.
The Locus Coeruleus degenerates in Alzheimer’s disease The Locus Coeruleus in Aging and Alzheimer’s Disease: A Postmortem and Brain Imaging staining of 6μm thick axial sections of pons to show locus coeruleus cells (denoted by *) of A) 87-year-old female with Alzheimer’s disease at death, Braak stage 6 compared to control brain of B) 86-year-old = huge lack of neuronal presence in Alzheimers- neurons dying throughout progression of disease
54
What is C-fos?
C-fos expression = early intermediate response gene that expressed in reponse to activity
55
How can C-fos be used to study the Locus Coeruleus?
* Can assess level of C-fos in Locus Coeruleus to determine neuronal activity * Under controlled conditions = low C-fos activation * Exposed to stress = dramatic increase in C-fos activation = suggesting increased activity in Locus Coeruleus neurons
56
Describe an experiment showing the effect of different stressors on the Locus Coeruleus + results
Predator odour affecting behaviour on mouse = change in activity of Locus Coeruleus neurons- specifically excitability = which has potential to produce fight/flight response in short term but in long term this degrades the neurons (Alzheimers) + induces an anxiety like behaviour = they go to places where they are less exposed
57
What does the activation of certain adrenergic receptors induce?
Activation of certain receptors induce expression of BACE1 which is directly involved in the production amyloid beta - this is released from the cell
58
What does the dysfunction of certain adrenergic receptors induce?
amyloid beta secretion or accumalation is held responsible for the degeneration effects in alzheimers disease
59
What are the cascades involved in the hyperactivity of the locus coeruleus?
Involved in neuroinflammation and accumalation of amyloid beta Also acts via microglia activation as these possess adrenergic receptors Also impacts blood brain barrier These all directly or indirectly result in accumulation of amyloid-beta = Alzheimers
60
In order for the body to function, what sort of levels should stress hormones be held at?
Stress hormones need to be held at an optimum range so the body can function Too high or too low for too long = dysfunction
61
What too low levels of stress hormones result in?
Also leads to dysfunction e.g. Addisons disease
62
What are the properties of mineralcorticoid receptors ?
* High affinity to stress hormornes * Activivated by low basal circulating levels of cortisol * So are activated in a circadian manner
63
Where are mineralcorticoid recepetors located?
MRs are located within cytosol and signals to the nucleus so orders gene expression directly Mainly limbic
64
What are the properties of glucocorticoid recpetors?
* Low affinity to stress hormones * Activated by circadian / stress high levels of cortisol * So lots of stress hormone present to induce response = so are activated predominantly in high stress levels
65
Where are glucocorticoid receptors found?
GRs can be located in the membrane or cytosol = so can directly alter gene expression as well as initiate GPCR receptor coupled cascades (cAMP) They are widespread

Disease in the brain (22 decks)

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