The neurobiology of stress and anxiety Flashcards
Epinephrine and norepinephrine are both ____
catecholamines
When does stress occur?
When the perceived demands of a situation exceed the perceived capabilities for meeting the demands
What is a negative physical and psychological stressor?
Physical abuse
Define the following terms:
- Stressor
- Stress-response
- Stress
Stressor: anything that disrupts the body’s physiological balance
Stress-response: the body’s adaptions designed to re-establish balance
Stress: general state of stressors provoking a stress response
Where is the anatomical localization of fear?
Basolateral, central and medial nuclei of the amygdala
Where is the anatomical localization of anxiety?
Basolateral amygdala projections to bed nucleus of the stria terminalis
What type of ‘hormones’ are released with activation of:
- HPA axis
- ANS
HPA: glucocorticoids
ANS: plasma catecholamines
Both are released during the fight or flight reactions
Describe the HPA axis
- Limbic system perceives stress and activates HPA axis
- CRH neurons in hypothalamus release CRH at median eminence
- CRH stimulates release of ACTH from cells in the anterior pituitary
- ACTH stimualtes both synthesis and release of GCs from adrenal cortex
- GCs act, in part to mobilize energy for the fight or flight response
- GCs also act to restrain the HPA axis by inhibiting the hormone release that the level of the hypothalamus, pituitary and higher brain regions (limbic system)
Where is NE and E released in the ANS during a stress response?
Norepinephrine: released at target tissue (eg. heart)
Epinephrine: released into bloodstream to act throughout the body
What parts of the adrenal gland secrete what? (3)
Capsule (zona glomerulosa): aldosterone
Adrenal cortex (zona fasciculata): glucocorticoids
Adrenal medulla: catecholamines
What are the two interrelated systems of the adrenal glands stress response?
Sympathetic-adrenomedullary (SAM)
Hypothalamic-pituitar-adrenocortical (HPA)
These balance each other and both are triggered by the hypothalamus
What is the rapid response to stress?
The sympathetic-adrenomedullary system is triggered by the hypothalamus and releases epinephrine and norepinephrine from the adrenal medulla.
This stimulates rapid mobilization of metabolic resources, increased HR, BP and blood glucose
What is the slower back-up response to stress?
What does this response target?
HPA activation
Adrenal cortex produces glucocorticoids and mineralcorticoids to metabolize fat and protein into glucose, suppress the immune response and raise BP
Targets glucocorticoid (type II: low affinity) and mineralcorticoid receptors (type I: high affinity) in the brain (especially at hippocampus) to change gene expression through dimerization of hormone/receptor complex, which recruits co-activators to stimulate gene transcription
Describe mineralcorticoid and glucocorticoid receptors in stress response
MR: type I: high affinity
GR: type II: low affinity
MR: mediates basal responses such as regulating neurotransmitters, BP and circadian rhythm
GR: responding to stressors when there are high level of glucocorticoids
GR effects, therefore, often oppose MR effects. This leads to vulnerability to stress, affected by ratio of GR to MR receptors and their activation.
As a monomer, GR (not MR) can inhibit gene transcription
Give the hypothalamus’s role in the stress response
- Secretes CRH, which causes the pituitary to secrete ACTH, which stimulates the adrenal medulla to release epinephrine, and the adrenal cortex to release glucocorticoids
The stress response maintains homeostasis over a far wider range of adaptive circumstances, and in responding to challenges (allostasis)
Describe cortisol’s effect on the immune system
- Reduces inflammation
- Reduces histamines
- Reduces immunity
Immune system is functionally suppressed
Epinephrine is released from sympathetic nerves, epinephrine from adrenal medula. Contrast their effects on the body.
Epinephrine:
- HR
- BP
- Lipid breakdown
- Peripheral vasoconstriction
- Coronary/bronchial dilation
- Liver/muscle Glycogenolysis
Norepinephrine:
- HR
- BP
- Lipid breakdown
- Peripheral vasoconstriction
List three deleterious effects of chronic stress
- Physical disease (ulcers, obesity, heart disease)
- Behaviour effects (inhibition of reproduction)
- Psychiatric illness (eg. depression)
List four processes that acute stress inhibits
- Mating behaviour
- Feeding
- GI processes
- Immune system
The purpose of the acute stress response is to increase levels of glucose within the bloodstream
Describe glucagon
Secreted by alpha cells in the pancreas. Causes release of glucose into bloodstream from stores (eg. glycogen)
Define the following
- Lipolysis
- Glycogenolysis
- Proteolysis
- Gluconeogenesis
Describe how E/NE/GCs effects each of these.
Lipolysis: Triglyceride breakdown into blood stream
Glycogenolysis: Glycogen metabolism and glucose into bloodstream
Proteolysis: Protein metabolism and amino acids flushed into bloodstream
Gluconeogenesis: Fatty acids and amino acids converted into glucose within the liver
E/NE: Adrenergic receptors (membrane), rapidly increases blood glucose through promotion of all of the above. Inhibits insulin release, promotes glucagon release.
Glucocorticoids: Intracellular receptors, increase synthesis of enzymes to increase gluconeogenesis (slower effect, but lasts longer)
Describe the effect of acute stress and vasopressin
Vasopressin released from axon terminals in posterior pituitary to stimulate water reabsorption in kidney. This increases blood volume and BP.
What are two forms of acute stress induced analgesia
Opiate dependent: enkephalins and beta endorphins released within brain to inhibit sensory processing
Opiate independent: Other NTs (eg. glutamate) inhibit processing painful info
Both forms occur during normal stress encounter. Adaptively, this is to allow fight or flight, rather than attention to tissue damage.
Give five behavioural effects of CRH release in the brain
- Inhibition of mating
- Inhibition of feeding
- Increased vigilance
- Increased freezing
- Increased behavioural reactivity
What is the adaptive significance of the stress response of inhibiting the immune system?
May protect the body from becoming too active and possibly attacking itself (autoimmune disease)
Describe stress-induced diabetes
- Decreases ability to utilize elevated blood glucose levels (hyperglycemia results) and insulin resistance
- Fatigue and muscle weakness (loss of protein - atrophy)
Describe stress-induced obesity
- Increased accumulation of fat as adipose tissue within the intra-abdominal area
- In adipose tissue, glucocorticoids inhibit the fat-releasing effect of insulin and promote the storage of fat as triglycerides
Give three causes of stress induced cardiovascular disease
- Hypertension
- Weakened vessels
- Cholesterol deposition and atherosclerosis
Described the effect of chronic stress on the GI tract
- Gastric ulcers
- Reduction in energetically costly thickening of stomach walls and mucus secretion
- Prostaglandins aid in repairing stomach ulcers, glucocorticoids inhibit prostaglandin synthesis and this may increase likelihood that gastric ulcers will form
How can chronic stress inhibit sex behaviour? Give two examples
Hypothalamus: CRH and beta endorphin release can inhibit GnRH
Pituitary: GCs act at the pituitary to decrease responsiveness to GnRH (fewer receptors), as a result, less LH and FSH will be secreted
Gonads: GCs act at level of gonad to decrease responsiveness to LH and FSH (fewer receptors), lower gonadal steroids are released.
Eg. High ranking female monkey can harass subordinates into anovulation. Multiple defeat can supporess testosterone secretion in males.
How can chronic stress inhibit growth and repair?
Somatostatin from hypothalamus inhibits release of GHRH (growth hormone releasing hormone).
Growth hormone stimulates the release of somatomedins from the liver. Somatomedins are growth factors that directly stimulate bone and cartilage growth. Chronic stress inhibits secretion of GH due to increased release of somatostatin
In children, stress induced inhibition of GH can impair physical growth: causing psychosocial dwarfism associated with severe emotional stress
How can chronic stress suppress nonspecific and specific defense systems?
Acutely and chronically
Acutely: GCs inhibit inflammation and limit proliferation of specific and nonspecific defense systems during an infection. Associated with decreased synthesis and release of interleukins and decreased synthesis of interleukin receptors
Chronically: Decreases in NK cells in cell mediated immunity and humoral mediated immunity. Decreased maturation of developing lymphocyte assocated with involution of immune tissue during chronic stress (eg. decrease in size of thymus gland)
Chronic stress can increase the likelihood of developing the common cold in humans!
True or false, chronic stress can increase the likelihood that tumors will develop in animals and also speed the growth of tumors.
True and observed in animals
Depression can increase risk in humans. Not all tumors may respond favourably to stress and results are subjective (based on ability to recall stress).
Describe dysregulation of the HPA axis in response to chronic stress
- Increased CRH present within the brain at PVN and amygdala
- Elevated GCs basally
- Adrenal gland hypertrophy
- Hippocampal damage, giving run away HPA activation
- Drug seeking behaviour
- Memory impairment
- Increased anxiety
- Learned helplessness
How can CRH antagonists treat depression and anxiety?
Limiting HPA axis dysregulation may limit development of depression and anxiety during chronic stress.
True or false, developing stress-related diseases is individualistic, some people may be more prone than others.
True..
Genetic predisposition (brain chemistry, personality etc.) interacts with previous experience to stress to determine how we cope with stress or react to stress, and whether we will develop stress-related disease.
What is the consequence of mutations on the glucocorticoid receptor protein, which decrease sensitivity to glucocortoids?
Glucocorticoid resistance syndrome
Dominant male monkeys have ___ levels of GCs compared to subordinate males
Dominant personality male monkeys have low levels of GCs compared to subordinate or dominant males without these personality traits
In an unstable environment, dominant males can have higher basal GC levels than non-dominant males.
In a stable environment, dominant males have less GC and are less stressed.
Describe Hans Selye’s general adaption syndrome
Predictable pattern of physical response to prolonged stress in animals and humans, comprised of three stages:
- Alarm (fight or flight, adrenal enlargement)
- Resistance (body adapts to stressor, allostasis)
- Exhaustion (body breaks down, adaption to stress is lost, energy stores depleted, damage, infection prevalent and wounds don’t heal)
What happens if a second stressor is applied to an animal in selye’s second stage (resistance)
The animal dies, as they exhausted their defense in adapting to the original stress
List five drugs associated with drug withdrawal and anxiety
- Alcohol
- Benzodiazepines
- Opiates
- Barbiturates
- Anti-hypertensives
Contrast a challenge with a threat
Challenge
- Heart rate up
- Heart contraction up
- CO up
- Vasodilation
- Blood to brain up
- Blood to muscles up
- Cognitive and physical performance increase
Threat
- HR up
- Decreased CO
- Vasoconstriction
- Less blood to brain
- Less blood to muscles
- Cognitive/physical decline
What is the notional model of emotions that arise from balance between challenge and coping ability (confidence)?
Apathy when challenge and confidence is low
Boredom/relaxation when challenge is low and confidence is moderate/high
Anxiety when challenge is high and confidence is low
Engagement/control when challenge and confidence is high
Arousal when confidence is moderate and challenge is high
Describe the effects of early life experience on the stress response
Mother grooming: development of GR, allowing HPA control
Insecure relationships: elevated cortisol and HR in response to HPA
Supportive child care: Reduced stress response and ability to elicit help by expressing negative emotions without triggering endocrine component of the stress response (modified limbic system reaction)
Describe stress related illness and socioeconomical standing
Stress-related illness worse for people at same income level who live in communities with high disparity, when compared with those who live in communities with uniform status.
Perceived low status is more important than actual status in predicting stress-related disease susceptibility
Give four reasons for mechanism of socioeconomic status (SES) effect on increased risk for stress-related disease
- Toxin exposure
- Nutrition deficiency
- Prenatal drug exposure (relatively small compared to other 3)
- Chronic stress
How does socioeconomic status predict hemispheric specialization of the left inferior frontal gyrus (Broca’s region) in young children?
Social causation: Evident from twin studies, experiences typical of SES levels effects brain development
Social selection: Differences in brain function predispose people to a particular level of socioeconomic success
Describe parental effects of development with Robert HInde’s theory
Evolution has shaped the ability of the offspring to use parental signals as a forecast of the quality of the environment into which they have been born. This signal will determine developmental outcome.
What are the effects of prenatal stress
Amygdala, frontal cortex, amygdala
Programming effect on HPA axis
Elevated glucocorticoid levels
What are the effects of postnatal stress
Hippocampus,
Differentiation effects on HPA axis
Elevated glucocorticoid release with maternal separation
Decreased GC release with severe trauma
What are the effects of adolescent stress
Frontal cortex
Potentiation/incubation effects on HPA axis
Elevated/decreases GC release
What are the effects of adult stress
Maintenance/manifestation effects on HPA axis
Cognitive decline/Depression: elevated GC release
PTSD: Decreased GC release
True or false, HPA axis activity can be transmitted across generations in an epigenetic manner
True
How do natural variations in maternal licking/grooming behaviour in the rat result in long term-effects on the HPA axis?
High: increased GR expression
Low: Decreased GR expression
Give a summary of high maternal care effects on the GR gene
What is the effect of trichostatin A (TSA) treatment? Met treatment?
- Transcription upregulated (increased NGFI-A binding)
- GR gene promoted
- GC receptors more expressed
- Less DNA methylation
- Less stress response
All these effects are mimicked by TSA (trichostatin A) treatment (to pups with low maternal care). The opposite effect is seen with Met treatment
How is infant abuse associate with BDNF in the rat brain?
Infant abuse associated with increased BDNF exon IV methylation in rate brain hippocampus, this effectively inhibits proliferation in the hippocampus.
Describe transmission of maternal behaviour in humans, primates and rodents
Humans
- Parental bonding
- Attachment
- Child abuse
Primates
- Mother-infant contact
- Maternal rejection
- Infant abuse
Rodents
- Individual differenes in contact and licking/grooming
Describe estrogen receptor DNA methylation in response to maternal care
Maternal care tactile stimulation
Low stimulation: methylation of ER and low expression in MPOA (medial preoptic area, limbic projections from BNST)
High stimulation: High ER expression in MPOA
What is the effect of low/high prenatal cortisol on child behaviour at 6-8 years?
Low prenatal cortisol: low anxiety/depression
High prenatal cortisol: high anxiety/depression
High prenatal cortisol also associated with adult clingyness, fear of school and nervousness.
How does intimate partner violence during pregnancy predict GR promoter methylation in children?
More methylation during pregnancy, but not after in mother.
The child shows more methylation (less GR expression) and this effect persists into adolescence
Describe hGR exon 1F promoter methylation and lifecourse
perspectives on health and disease?
- CpG methylation patterns in transcription factor binding sites on the GR exon 1F promoter are both stochastic and unique to the individual in healthy human subjects
- Neonatal methylation at the 5’ CpG dinucleotide in an NGFI-A binding site is possibly linked
to maternal mood and risk of HPA function in the developing infant - NGFI-A binding sites on the hippocampal hGR exon 1F promoter are hypermethylated in suicide victims with a history of child abuse by comparison to controls (victims of sudden,
accidental death with no history of child abuse)
What is the takehome message of supportive care during development?
“One of the most interesting findings emerging from the research … is
that in the absence of supportive care, stressors experienced during
sensitive periods of development can … leave permanent imprints in
the neural substrate of emotional and cognitive processes. … the
nervous system of mammals carries their singular epigenetic history
and expresses it in unique but predictable ways”.
