HPA axis (finished) Flashcards
What makes up the HPA axis?
Hypothalamus, Pituitary gland & Adrenal glands
What happens in the HPA axis?
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
What does CRH stand for?
Corticotropin releasing hormone
What does ACTH stand for?
Adrenocorticotropic hormone
What is the HPA axis like in depressed patients?
They have a hyperactivation (about 50%) of the HPA
What kind of loop is the HPA axis and what is this like in depression?
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
How do depressed patients display HPA hyper-activation?
- ↑ 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
How does CORT (endogenous glucocorticoid hormone) differ in humans compared to rats, mice, birds & reptiles etc?
- Humans have CORTISOL
- Other animals have CORTICOSTERONE –> this lacks an OH grp compared to cortisol (only difference)
What does acute stress response do to ACTH & CRH?
Increases the levels of them- quite dramatically (8x)
Is the structure of CRH AND ACTH similar?
Similar structure- only a few different amino acids dependent on different species
What is the structure of CRH?
A 41 amino acid chain
What is the structure of ACTH?
A 30 amino acid sequence
Describe the cycle of the 2 peptides CRH and ACTH
Changes within the day- 24 hour cycle
Lowest point of the night = low peptides levels
In the day = larger levels of peptides present
What are the half lives of ACTH & CORT?
Relatively long:
ACTH / CRH = 19 min
CORT = 49 min
What are the levels of ACTH & CORT during acute stress?
ACTH = 40-80 pg/ml
CORT = 20-35 ug/100ml
Where are the adrenal glands located?
Above the kidneys
(They are small endocrine glands essential for life)
What are the 5 zones of the adrenal glands called (top to bottom)?
- 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
What is the largest past of the adrenal glands?
The medulla
What is also running through the different zones of the adrenal glands?
Capilliaries
What is the role of the 3 zones of the adrenal cortex?
Name them
They produce the stress hormones (cortisol or aldosterone)
These are known as steroids
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
Where are steroids and catecholamines made in the adrenal glands?
Steroids = top 3 zones (known as the adrenal cortex)
Catecholamines = medulla
What are the outer and inner compositions of the adrenal glands called?
Outer comp = adrenal cortex (top 3 zones)
Inner comp = medulla
What are the two steroids produced by the adrenal cortex & give examples of these?
Zona glomerulosa = Glucocorticoids e.g. cortisol
Zona fasciculata = Mineralocorticoid e.g. aldosterone
What does the medulla produce? Give examples
Catecholamines
E.g. noradrenaline & adrenaline that are released into blood
(As a consequence of stress activation)
Where are Chromaffin cells found?
In the medulla of the adrenal glands
What 2 things are the adrenal glands controlled by?
Dual control by: autonomic & endocrine
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
During stress, what happens in the HPA axis?
Increased responses = enhances activities of both pathways
Name 3 different forms of stress
Physical
Metabolic
Psychological
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
Are the effects of cortisol beneficial?
Yes in short term activation but in the long term activation = detrimental negative effects on the body
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
The HPA axis has changes that occur in stressful events, when do these changes also occur?
Circadian events that are essential for survival
What is the trigger for changing the activity of the HPA axis?
Suprachiasmatic nucleus (SCN) as it receives the impulse from light activity
What is the SCN?
= central pacemaker of the circadian timing system regulates most circadian rhythms in the body
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
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
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)
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
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
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
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
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
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
What produces Glucocorticoids e.g. cortisol Mineralocorticoid e.g. aldosterone?
medulla in adrenal glands
What are the specific receptors in which mineralcorticoids and glutocorticoids act?
MR = mineralcorticoid receptors
GR = glutocorticoid receptors
Where are GRs and MRs present?
widespread expressed throughout the brain:
- high density in hippocampus and hypothalamus and brain stem
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
What is the locus coeruleus?
= nucleus located in the brain stem which increases activity in response to stress
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
Where do noradrenergic neurons originate?
Predominantly in the locus coeruleus
What has the dysfunction of noradrenaline signalling been implicated in?
Alzheimers
Ageing related dysfunction and neurodegeneration
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
What is C-fos?
C-fos expression = early intermediate response gene that expressed in reponse to activity
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
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
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
What does the dysfunction of certain adrenergic receptors induce?
amyloid beta secretion or accumalation is held responsible for the degeneration effects in alzheimers disease
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
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
What too low levels of stress hormones result in?
Also leads to dysfunction e.g. Addisons disease
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
Where are mineralcorticoid recepetors located?
MRs are located within cytosol and signals to the nucleus so orders gene expression directly
Mainly limbic
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
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
