The neurobiological aspects of stress Flashcards
What are stress responses?
Physiological and behavioural responses arising
- in response to anything that threatens the homeostasis of the organism
- in an attempt to reinstate equilibrium
e.g. fight, flight or freeze
What causes stress?
Any circumstances that either
- threaten individual’s well-being
- or that the individual perceives as threatening to their well-being
To whom has the concept of stress been attributed?
Hans Selye
- Australian-Canadian endocrinologist of Hungarian origin
For what has Hans Selye been nominated the Nobel Prize between 1949-1953?
Nominated for Nobel Prize 17 times for his:
- work on endocrinology and adaptation syndrome
- contributions to the isolation of steroid hormones
- formulation of stress reactions
What was Hans Selye’s experiment on stress responses (1974)?
> Neurochemical experiment
- rats were injected with new ovarian extract
> Environmental experiment
- rats were placed on roof in winter, others in boiler room, others subjected to forced exercise or surgical procedures
-> changes observed were a general response to the different types of stress rats were subjected to
=> Selye called it the “general adaptation syndrome”
= stress response, producing stress hormones
What are glucocorticoids?
Stress hormones
- glucose + cortex + steroid
- regulate glucose metabolism
- synthesised in adrenal cortex
- classified as steroid chemical structure
What mediates the action of glucocorticoids?
2 types of corticosteroid receptors:
- Mineralocorticoid receptors (MR)
- classical glucocorticoid receptors (GR)
What characterises mineralocorticoid receptors (MRs)?
- High affinity for endogenous glucocorticoids
- Activated by low basal cortisol concentrations
What characterises glucocorticoid receptors (GRs)?
They are ligand-activated nuclear transcriptions factors
- Low affinity for endogenous glucocorticoids
- Activated by high cortisol concentrations
How do glucocorticoids regulate gene transcription?
Stress -> adrenal cortex -> high cortisol concentrations
-> activates GRs
- Upon ligand binding from cortisol, GR residing in cytoplasm, in association with chaperone proteins, translocates in nucleus
- Binds to glucocorticoid response elements (GREs) present on DNA
- > regulates gene transcription
How does the hypothalamus-pituitary-adrenal (HPA) axis produce cortisol?
> Paraventricular nucleus (PVN) o hypothalamus secretes corticotropin-releasing hormone/factor (CRH/CRF) and arginine-vasopressin (AVP)
> CRH and AVP stimulate secretion of adrenocorticotropic hormone (ACTH) from pituitary gland
> ACTH travels to adrenal glands (adrenal cortex, above kidneys) to promote synthesis and release of cortisol
What is the role of cortisol?
> Enables body to maintain adequate and steady blood sugar levels
- by releasing stored glucose from liver for energy
- causing suppression of immune system
> Cortisol is part of endocrine system
- acts in different ways in neurotransmitters of nervous system
What is the consequence of excessive levels of circulating cortisol?
Negative feedback regulation
- feedback inhibition of secretion of adrenocorticotropic hormone (ACTH) from pituitary glands and corticotropin-releasing-hormone (CRH) from hypothalamus
- > decreasing cortisol production
What is the negative feedback regulation of cortisol?
Excessive levels of circulating cortisol signal the brain to regulate cortisol production
What is the endocrine system made of?
Hormones, glands and receptors
How does the endocrine system work?
Stimulus -> endocrine cells release hormones into blood vessels
-> hormone-induced response at protein or genetic level
What characterises the transmissions in the endocrine system?
Chemical impulses transported by blood
- slow
What characterises endocrine responses and effects?
- Involuntary responses
- Slow and short or long lived effects
What is the nervous system made of?
Neurones
How does the nervous system work?
Stimulus -> neuronal cell receives signal from dendrites
- signal travels along axon
- neuronal responses in synapses
What characterises the transmissions in the nervous system?
Neurotransmission
- electrical impulses transmitted by neurons
- rapid
What characterises neuronal responses and effects?
- Voluntary or involuntary responses
- Fast and short lived effects
What is the role action of the endocrine and nervous systems in normal conditions?
Maintain constant internal environment, while being able to respond and adapt to external events
What is the Recent Life Changes Questionnaire (RLCQ)?
Tool to assess stress levels by taking into account the presence or perception of recent life events
- uses a list of most common sources of stress as evaluation tool
- includes 5 categories:
How is the Recent Life Changes Questionnaire (RLCQ) composed?
> Uses a list of most common sources of stress as evaluation tool
> Includes 5 categories:
- Work
- Home and Family
- Health
- Personal and Social
- Financial
> Scoring:
- score each event according to severity using Life Change Units (LCUs)
- add up all LCUs to get final score
> Individual reaction to stress is key factor
What characterises the acute stress response?
- Increased blood pressure and blood flow to the brain
- Faster breathing
- Slower digestion
- Increased perspiration
- Increased levels of cortisol in saliva
- Increased muscle tension
- > mobilisation of glucose and other energy molecules to fuel muscles for fight-or-flight response
- > focuses aspects of memory and cognition, sharpening detection of sensations and increasing alertness
What are the effects of chronic stress?
- Digestive problems
- Increased stomach acidity levels
- Increased cholesterol and fatty acids
- Increased levels of blood pressure and blood sugar
- Menstrual cycle irregularities in women
- Reduced sperm count and testosterone levels in men
- Increased chances of developing infections (weakened immune system)
- When severe, can lead to depression
What did Kendler and colleagues find about the vulnerability factors in the relationship between stressful life events and depression?
> 7500 twins from population based sample
> Overall increase in stress levels
> Individuals with low levels of neuroticism were much less sensitive to depressogenic effects of adversity
vs. those with high levels of neuroticism
What are the observed effects of high glucocorticoid levels in animal studies?
- Depression-like behaviour
- Decreased neurogenesis
- Monoamine dysfunction
- Impaired synaptic plasticity
- Reduced volume of hippocampus
Same changes are thought to be present in brains of depressed patients
What are the effects of high glucocorticoid levels in humans?
> When treated with synthetic glucocorticoids, might lead to:
- development of manic symptoms at start of treatment
- development of depressive symptoms after few weeks of treatment
> Patients with Cushing’s syndrome (chronic hypercorticolism) demonstrate high rates of depression
When are synthetic glucocorticoids used?
To treat many inflammatory conditions and autoimmune diseases
What is the action of the hypothalamic-pituitary-adrenal (HPA) axis under normal conditions?
Negative feedback regulation of HPA axis
-> feedback inhibition stops production of cortisol
What is glucocorticoid resistance?
Reduced cortisol effects, believed to be related to impaired function of glucocorticoid receptor (GR)
What could cause a failure in the function of the glucocorticoid receptors (GRs), hypothesised in depression?
Reduced glucocorticoid binding to the GR
OR reduced GR expression
- > increased levels of cortisol don’t send feedback to brain, to stop secretion corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH)
- > cortisol synthesis and release continues
In which cases has the alteration of the hypothalamic-pituitary-adrenal (HPA) axis been observed?
> HPA hyperactivity and hypercorticolism
- associated with MDD and depression with melancholic features (unreactive mood)
> HPA hyperactivity and hypocorticolism
- associated with atypical depression (reactive mood)
How are stress effects neurobiologically evaluated in animals?
- Blood samples
- Brain samples
How are stress effects neurobiologically evaluated in humans?
- Blood
- Urine
- Saliva
- Hair
- Stem cells
How do corticoids affect neurogenesis in rodents?
> Corticosterone:
- negatively affects hippocampal neurogenesis
- increased corticosterone -> decreased neurogenesis
> Adrenal steroids:
- regulate both proliferation and differentiation of new neurons in dentate gyrus
- adrenalectomy (removal of adrenal glands) -> no corticosterone -> increased neurogenesis
What is corticosterone?
Main glucocorticoid in rodents
- affects hippocampal neurogenesis
What did Tanapat and colleagues (2021) find on the relationship between psychological stress and neurogenesis?
> When rats were exposed to fox door:
- decreased number of proliferating cells in dentate gyrus (dependent on stress-induced rise in adrenal hormones)
- increased levels of circulating corticosterone
- decreased number of new granule cells was transient
- > did not cause permanent damage
> When rats subjected to adrenalectomy:
- no suppression of cell proliferation was found
What was the novel theory of Jacobs and colleagues on neurogenesis and depression (2000)?
Altered rates of neurogenesis in adult hippocampus might underlie the development of major depression or hinder one’s recovery from it
- stress + raised glucocorticoids
- > decreased neurogenesis and increased depression
- exercise + antidepressants
- > increased neurogenesis and decreased depression
=> high cortisol levels and adversity are risks for depression, whilst exercise and antidepressants hasten recovery in humans
What is the novel cellular pathway revealed by Wohleb and colleagues (2018) which contributes to the pathophysiology of stress-induced disorders?
Stress-induced signalling between neurons and microglia
> Mice intermittently exposed to stressful conditions
= chronic unpredictable stress
-> Increased messenger RNA levels of colony stimulating factor 1 (CSF1)
-> Changes in microglia corresponded with reduced dendritic spine density on pyramidal neurons in layer 1 lf medial PFC
= reduction in synaptic connections in PFC (associated with major depression in clinical studies)
-> When preventing neurons from producing CSF1 by viral knockdown, mice exposed to chronic stress DID NOT develop symptoms of anxiety or depression
=> Interrupting stress-induced signalling between neurons and microglia might be an effective treatment for anxiety and depression
What did Anacker and colleagues (2013) show about the effects of high cortisol levels using a clinically relevant model of human hippocampal progenitor cells?
- In cells treated with high doses of cortisol: reduction in neurogenesis
- Cells stained for BrdU showed reduction in Dcx-positive neuroblasts (doublecortin) and MAP2-positive neurons (microtubule-associated protein) = growth factors
What are the effects of antidepressants on glucocorticoid receptors shown (Anacker et al., 2011)?
Using dexamethasone: synthetic glucocorticoid specific GR-agonist
- demaxethasone decreased number of MAP2-positive neurons by 27%
- decreased Dcx-positive (Doublecortin) neuroblasts by 25%
- co-treatment of cells with selective serotonin reuptake inhibitor sertraline and demaxethasone abolished the reduction of MAP2- and Dcx-positive cells
What is the cortisol awakening response (CAR)?
Sharp increase of cortisol at awakening, for 35 minutes
What has been found on the cortisol circadian rhythm?
> Cortisol awakening response showed unique associations with range of lifestyle factors and psychological traits
(often different from those observed over remainder of day)
> High cortisol awakening response may be indicative of an increased biological vulnerability for depression
What is the condition for collecting saliva samples to measure cortisol levels?
Participants must refrain from eating, smoking, drinking or brushing teeth, 15 minutes prior to collection
What is the limit of saliva samples for measuring cortisol levels?
Saliva samples only allow for single measurements, reflecting short-term levels of cortisol
How can long-term levels of cortisol be measured?
With urine or hair samples
What is the importance of measuring the long-term levels of cortisol in the aetiology of chronic diseases?
Cumulative effect of frequent HPA axis activation may be associated with maladaptive effects of the organism
What has been observed on cortisol in postnatal depression (Taylor et al., 2009)?
- Non-depressed postnatally women showed pattern of cortisol secretion over the day similar to non-perinatal controls
- Depressed women showed significantly higher cortisol levels at awakening and no increase 30 minutes later
=> lack of morning cortisol rise in depressed women group is similar to that reported for PTSD and chronic fatigue syndrome
- may reflect a response in vulnerable women to marked cortisol withdrawal that occurs after delivery
What did Weger and colleagues find on the vulnerable phenotypes for stress-induced depression (2018)?
- Highly anxious individuals show behavioural alterations and more reactive physiological stress responses
- Molecular variations (due either to genetic or epigenetic factors) in key neurobiological systems (e.g. NT systems and HPA axis) might define high anxiety trait in people
- Only in combination with suboptimal environmental conditions does high anxiety trait provide a vulnerability phenotype for development of psychopathology (anxiety disorders, depression)
- > It is not stress that kills us but our reaction to it
