Stress

• • Stressor: an external event, a thing that stresses
• • Stress: internal perception of stressor
• • Stress response: what we do in response to stressor - physiological/behavior
• • Acute stress: short term, happens quickly
  • Ex: predator attack, finals week
  • Activates the sympathetic nervous system (fight/flight)
  • Fight or flight recall:
  • Increases availability to energy (inc glucose)
  • Increases oxygen intake
  • Increased blood flow (via increased heart rate)
  • Inhibition of parasympathetic behaviors (rest/digest)
  • Altered (not non functioning) immune functioning 
  • Ex: if wounded immune cells are mobilized to the skin in case there is a wound
  • Enhancement of memory and sensory processing
  • Ex: to remember if the area is dangerous
• • Chronic stress: ongoing, long and happens slowly
  • Ex: long drought, long time health complications
  • Activates the HPA (hypothalamic pituitary adrenal) axis
• • Acute stress response is only beneficial in short term situations - activation of acute stress response for long periods of time is not good
  • Increases availability to energy (inc glucose) → diabetes
  • Increases oxygen intake
  • Increased blood flow (via increased heart rate) → high blood pressure
  • Inhibition of parasympathetic behaviors (rest/digest)
  • Ex: reduced reproduction → infertility
  • Altered (not non functioning) immune functioning → low resistance 
  • Enhancement of memory and sensory processing → neural degeneration
  • Too much excitement/glutamate → makes neurons vulnerable
• • Adrenal hormones and how they coordinate the stress response
  • Adrenal glands sit on top of the kidneys and consist of 2 layers
  • Cortex (the bark)
  • Medulla (the center)
• • Cortex (the bark)
  • The layers and what they produce:
  • Zona glomerulosa: aldosterone/mineralocorticoid: regulates salt+water in kidneys (where salt goes, water follows)
  • Zona fasciculata: Corticosterone (in animals)/Cortisol → glucocorticoids
  • Zona reticularis (not everything has this): DHEA (T precursor)
• • Medulla (the center)
  • Produces:
  • Catecholamines (a type of monoamine): a hormone from amino acids (usually tyrosine) 
  • Ex: epinephrine, norepinephrine etc → have their own g protein coupled receptors
  • Catecholamines does what you expect (inc heart rate, blood sugar, etc)
• • Hypothalamic Pituitary Adrenal axis
  • Stimuli → appraisal by hypothalamus → determines it is a threat → HPA response 
  • Hypothalamus → releases corticotrophic releasing hormone (into shared portal system) → anterior pituitary → releases ACTH → adrenal cortex → cortisol
  • Cortisol then acts as a negative feedback to both ant. pit. and hypothal. → reduces both ACTH and CRH
• • Adrenocortical hormones
  • Must be catalyzed by enzymes (like how DHEA needs 3b-HSD to get to T)
  • Progesterone can be turned into corticosterone/cortisol (all species have aldosterone regardless of glucocorticoid, humans must still have a little corticosterone to make aldosterone)
  • There are mechanisms to remove cortisol/degradation of signals 
• • Glucocorticoid transport
  • Lipophilic - requires transport protein (corticosteroid binding globulin) to travel through blood
  • CBG can bind 1 steroid per 1 protein and binds about 90% of them
  • Binding to CBG prevents glucocorticoid from going through blood brain barrier → the steroid can't bind to receptors, but free steroids can: there is a large cortico storage in the blood 
• • How to tell what receptor?
  • Check what speed it's going at
  • Things like cortisol bind to a large protein: cannot pass membrane and thus cannot be intracellular and is probably acting at the membrane
  • Adding transcriptional inhibitor: if it still works in the presence of inhibitor it’s non genomic and thus in the membrane
• • Intracellular: in the cytoplasm or cell nucleus, it regulates gene expression by regulating transcription factors, SLOW acting (for genes to do transcription and lation, it takes time)
  • Glucocorticoid receptor (GR): only for glucocorticoids → has lower affinity for glucocorticoids, only occupied when MRs are full (when stressed)
  • Mineralocorticoid receptor (MR): for glucocorticoids and aldosterone → has higher affinity for glucocorticoids (more likely to bind when normal)
  • Hormone response element (HRE): GR and MR bind to this to regulate gene expression, HRE are on the promoters of genes
• GRE (glucocorticoid response element) vs MRE (mineralocorticoid receptor) → when unbound it has no effect, GR and MR can inc/dec expression
• Membrane bound: on plasma membrane, releases enzymes/kinases as a secondary messenger for the cascade, FAST acting
• • Membrane steroid receptors: case study - Male newt sexual behavior + corticosterone
  • % clasping to a female vs time after injection of placebo/cortico
  • Ovt, control males % have clasped continues to rise
  • Ovt, cortico males remain 0 the entire time 
  • Occurs in 10 mins: non genomic = membrane receptor
• male newt case study

  • What receptors though? (ligand binding assay)
  • Using tridiated H - corticosterone to find binding in the membrane
  • Using both labeled and unlabeled as it is lipophilic and may stick to the plasma membrane
  • Also using more unlabeled than labeled: if the receptor is specific, non labeled corticosterone will bind with the receptors, causing for labeled to be unable to bind (it outcompetes it)
  • Non-specific: sticking in the membrane not being specific (no limit)
• • It shows that specific binding will have a high amount of bound cortico but it also quickly plateaus
  • Total binding = specific and non specific binding
  • Graph: bound to membrane cortico vs amount added
  • Non specific: expected - to continue going up with amount added
  • Specific: shows saturation, a plateau occurs as concentration goes up - represents receptors being used
  • Take away: they show it is a rapid effect and binds to neuronal membranes
• • Stress and hippocampus
  • Particularly sensitive to cortico, provides negative feedback to the PVN and breaks glucocorticoid production
  • Contains many GR and MR
  • Sensitive to chronic stress - elevated levels of glucocorticoids → dendritic atrophy → vulnerability to cell death (vulnerability to apoptosis or vulnerability to overstimulation/other insults)
  • Damage to hippocampus → damage to breaks → more cortisol → repeat
• • Hippocampal dendritic atrophy
  • Use of golgi stains to visualize neurons
  • Showed that animals under chronic stress - subordinate, not dominant - had shrunken dendritic trees 
  • In amygdala, it can show dendritic growth bc its purpose in emotional responses
• • Consequences of chronic stress
  • Unipolar depression/Major depressive disorder: severe symptoms for 2+ weeks
  • 5-10%, 2x more prevalent in women
  • Appears as periodic episodes
  • Major cause of disability and is very costly
  • Is not caused by a single gene mutation - 60% of both identical twins having it, 20% for fraternal twins
  • Stress: early life stress may lead to chronic stress → depression
  • May also cause epigenetic changes and create vulnerability for a second hit
• Consequences of chronic stress

  • Dysthymia: less severe symptoms for 2+ years
  • Symptoms: 
  • reduced/absence of happiness/mood/pleasure(anhedonia)/motivation (anergia)
  • Low self esteem
  • anger/guilt
  • Disturbances in sleep or eating
  • Difficulty in concentration/memory  - cognitive impairments
  • Suicidal thoughts
• • Social readjustment scale:
  • Giving people a list of life events and rate on how much they have to adjust their life afterwards
  • Not all events are negative but all things can cause stress - it is an internal perception
  • Ex: being fired from a job you hate vs love
• • Cortisol and depression
  • Looking at cortisol in the blood of hospitalized depressive patients, hospitalized non depressive patients, normal controls
  • Depressed show a huge elevation in cortisol - hypercortisolemia
  • Also implies impaired negative feedback
• • Measuring negative feedback impairment: Dexamethasone (DEX) suppression test
  • DEX; GR agonist (it binds to GR and outcompetes glucocorticoids for binding)
  • Looked for reduced GR in brain or pituitary, measured blood cortisol throughout day
  • Results: 
  • Controls:
  • No DEX: show an increase in cortisol to wake up and peak @ meal times
  • DEX: show cortisol is low all day
  • Depressed:
  • No DEX: irregular cortisol all the time
  • DEX: show suppression of irregularity, peaks later in the day but only sometimes - looks like normal patient (kinda)
• • Inflammation and depression - recall the brain is connected to the rest of the body
  • Inflammation: leaky blood vessels releasing immune cells, happens a lot
  • Characterized by redness, warmth, swelling, pain
• • Depressed patients show elevated inflammation markers
  • Ex:
  • More proinflammatory cytokines in blood
  • Cytokines: hormones of immune system
  • Suggestions of neural inflammation as well - hard to be assess markers of brain inflammation
  • Ex: depressed patients have microglia that look altered
  • Inflammation triggers glucocorticoid levels
  • Cytokines → hyptothal → CGs –| negative feedback to limit inflammation
• • Immune system: basics
  • To defend the body from anything
  • Needs the ability to differentiate between self and not self → done by leukocytes
• innate/non-specific immunity:

  • Rapid, quick and dirty - non specificity = can cause harm to self
  • First line of defense, uses big eaters ex: macrophages
• Specific/cell adaptive immunity

  Slow, needs to develop
• Specific/cell adaptive immunity

  • Antibody mediated (humoral/in the blood) immunity
  • Involves B cells (lymphocyte) → produces antibodies upon re-exposure to pathogen

  Ex: Antibodies will bind to pathogen, signaling to macrophage to eat it → a messenger will present a piece of the pathogen (antigen presentation) to a T helper (CD4+) which will produce pathogen relevant cytokines (ex: b cells) to attack
• Specific/cell adaptive immunity

  •  Cell-mediated immunity
  • Using T cells (lymphocyte) → kills pathogens upon re-exposure

  Ex: also have antigen presentation to T helper → creates cytokine that causes clonal multiplication of relevant cytotoxic T cell
• • Specifics: lymphocytes - B cells → B for bone marrow
  • Originate in bone marrow, B cells mature there
  • For antibody mediated
  • Antibodies: proteins that bind to antigens
  • Antigens: molecules on bacteria/viruses
  • Antibodies tell macrophages what to kill
• • T cells → T for thymus
  • From bone marrow to mature in thymus
  • For cell mediated
  • Cytotoxic: attacks pathogens directly 
  • Helper: help other T cells or B cells to multiply
• • Cytokines: small proteins produced by leukocytes and other cells to combat infection and inform the brain
  • Cytokines stimulate production of prostaglandins in the brain
  • Prostaglandins produce fever and sleepiness → forcing the body to conserve energy