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What does cortisol do in GC signaling?
- Sits around in plasma with carrier protein
- Enters cell through membrane
- Binds to GR
- Changes its conformation
- HSP90 dissociates
- NLS visible now
- NLS makes GR's dimerize
- Travels to and enters nucleus
- Binds to glucocorticoid responsive element on DNA at DNA binding domain
- Helps with transcription and activates gene expression
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What is the hypothesis for genetically manipulating GC signaling with 11-beta HSD?
- 11-beta HSD will degrade cortisol into cortisone
- Wont' bind to GR
- GR won't enter nucleus
- Nothing happens
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What is the hypothesis for genetically manipulating GR signaling by using a GRbeta instead of GRalpha?
- dominant negative GR will antagonize GR
- Cort will bind to GR but dimerizes with dnGR, so nothing happens
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What happens when there's a high amount of estrogen in the hippocampus?
High estrogen protects the hippocampus
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How does high estrogen protect the hippocampus?
- Increases neuronal survival of necrotic insult
- Enhances dendritic sprouting and synapse formation
- Strengthens Long Term Potentiation (LTP)
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What is the hypothesis for genetically manipulating GR signaling with ER/GR?
- ER/GR will eliminate cort effects, and mimic estrogen
- Cort enters cell
- Binds to both GR and ER/GR
- ER/GR dimerizes
- ER/GR dimer enters cell but binds to estrogen responsive element (ERE) instead of GRE
- Activates estrogen responsive gene expression
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Summarize the three genetic manipulations of GC's signaling
- Inactive metabolite: Corticosterone enters cell; interacts with 11-beta HSD to make 11-dehydrocorticosterone; doesn't bind to GR
- Dominant negative: Corticosterone enters cell; binds to form GR/GRbeta dimer; doesn't go into nucleus
- Convert response: Corticosterone enters cell; binds to ER/GR; enters nucleus; binds to ERE; activates estrogen responsive gene expression
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How would you get certain engineered proteins into brain cells?
- New genetic material
- Use either virus or stem cells
- Inject into brain
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How are vectors neuroprotective?
- Vectors protect against cell death in epilepsy
- Vectors protect against stress effects on stem cells in the hippocampus
- ER/GR expression enhances spatial memory performance and blocks the impairing effects of GCs on such performance
- ER/GR chimera protects against stroke-induced cell death, blocks fear memory consolidation
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What is the normal fight or flight stress response pathway?
- Stressful signal
- HPA axis
- Increases heart rate, blood pressure, and blood flow to muscles
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What is the short term stress pathway?
- Stress signal in hypothalamus
- Nerve impulses to spinal cord
- Preganglionic sympathetic fibers to adrenal medulla
- Catecholamines released (epinephrine and norepinephrine)
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What is the long term stress pathway?
- Stress signal in hypothalamus
- CRH (corticotropin-releasing hormone)
- Corticotrope cells of anterior pituitary
- ACTH released
- To target in blood
- Adrenal cortex
- Mineralocorticoids (MC) and Glucocorticoids (GC) released
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Describe the roadmap to neuroanatomy.
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What is the autonomic nervous system (ANS)?
- Division of the peripheral nervous system
- Influences the function of internal organs
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What are some of organ functions that the ANS influences?
- Heart rate
- Digestion
- Respiratory rate
- Pupillary response
- Urination
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What are the 2 divisions of the ANS?
- Sympathetic
- Parasympathetic
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What is the parasympathetic division generally responsible for?
Rest and digest
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What kinds of thingds does the parasympathetic division do?
- Constricts pupil
- Stimulates saliva production
- Constricts bronchi
- Slows heart
- Stimulates stomach, pancreas, and intestines
- Stimulates urination
- Promotes erection of genitals
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What is the sympathetic division generally responsible for?
Fight or flight
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What kinds of things does the sympathetic division do?
- Dilates pupils
- Inhibits saliva production
- Dilates bronchi
- Accelerates heart
- Simulates epinephrine and norepinephrine release
- Stimulates glucose release
- Inhibits stomach, pancreas, and intestines
- Inhibits urination
- Promotes ejaculation and vaginal contractions
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What hormones does the adrenal medulla release?
- Adrenaline (aka epinephrine)
- Noradrenaline (aka norepinephrine)
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Which amino acid are adrenaline and noradrenaline derived from?
Tyrosine
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What is the splanchnic nerve?
Neurons that are part of the sympathetic branch of the nervous system
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The adrenal medulla is innervated by which nerve/set of neurons?
Splanchnic nerve
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What happens when the splanchnic nerve is stimulated following a physical or mental stress?
Chromaffin cells in the adrenal medulla release adrenaline (80%) and noradrenaline (20%) into the blood stream
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What do the hormones adrenaline and noradrenaline bind to in the blood?
- Adrenergic hormones
- Transmembrane proteins in the plasma membrane of many cell types
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What are adrenergic receptors?
- Transmembrane proteins in the plasma membrane of many cell types
- Class of G protein-coupled receptors
- Targets of the catecholamines, especially noradrenaline and adrenaline
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Associated nerves and prevertebral ganglia send out what kind of fibers?
Sympathetic fibers
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Associated nerves and terminal ganglia send out what kind of fibers?
Parasympathetic fibers
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What are chromaffin cells?
- Neuroendocrine cells in the adrenal medulla
- Release adrenaline and noradrenaline in response to neural input
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The binding of a catecholamine to an adrenergic receptor will generally stimulate which nervous system?
Sympathetic nervous system
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What are the effects of adrenaline and noradrenaline?
- Increae in heartbeat (resulting in increased blood pressure)
- Blood shunted from the skin and viscera to the skeletal muscles, coronary arteries, liver, and brain
- Rise in blood sugar
- Increased metabolic rate
- Bronchi dilate
- Pupiles dilate
- Hair stands on end (goosebumps)
- Increased ACTH secretion from the anterior lobe of the pituitary
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What is the longer pathway for the fight or flight stress response?
- Stress signal
- Hypothalamus
- Stimulates splanchnic nerve
- Stimulate adrenal medulla
- Release adrenaline and noradrenaline from chromaffin cells
- This is all short-lasting though
- Either go directly to muscles and get response (high BP, muslces, etc.) or go to HPA axis then the muscles
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Adrenaline and NE effects are immediate, and ___________?
Short-lasting
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What is allostasis?
- Maintianing stability (or homeostasis) through change
- The process of achieving stability, or homeostasis, through physiological or behavioral change
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When does an allostatic sttate occur?
When set-points vary outside homeostatic limits and results in an imbalance of the primary mediators
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How can allostasis be carried out?
- By means of alteration in:
- HPA axis hormones
- The autonomic nervous system
- Cytokines
- Or a number of other systems
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Allostasis is generally adaptive in the ____-term.
short
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Why is allostasis essential?
In order to maintain internal viability amid changing conditions
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Who made the term allostatic load?
McEwen and Stellar (1993)
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What is allostatic load?
- The physiological cost of making long-term adaptive shifts across a broad range of systems to match internal functioning to environmental demand
- 'The cost of adaption'
- The wear and tear to the body systems that result from maintenance of allostatic changes over a long period
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What is homeostasis?
The regulation of the body to a balance, by single point tuning
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What are examples of homeostasis?
- Blood oxygen level
- Blood glucose
- Blood pH
-
What's an example of the body maintaining homeostasis with body temp?
- When walking through a hot desert, the body will sweat
- They will quickly become dehydrated
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How is allostasis different from homeostasis in regards to the desert/dehydration example?
- Allostasis is adaption but in regard to a more dynamic balance
- In dehydration, sweat occurs as only a small part of the process
- Many other systems are also adapting their functioning, to reduce water use and to support the variety of other systems that are changing to aid this
- Kidneys may reduce urine output, mucous membrane in the mouth, nose and eyes may dry out
- Urine and sweat output will decrease
- The releae of vasopressin (AVP, or ADH) will increase
- Veins and arteries will constrict to maintain blood pressure with a smaller blood volume
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What is allostatic overload?
Pathological condition that could develop
-
Every system in the body responds to acte challenge with what?
Adaption
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What results from acute challenges becoming chronic?
Allostatic overload
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What's the point of allostatic load resulting from acute challenges turning chronic?
- Nothing, serves no useful purpose
- Just predisposes individuals to disease (overload)
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What are the different types of allostatic load?
- Frequent activation of allostatic systems
- Lack of adaption to repeated stressor
- Failure to shut off allostatic activation after stress
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Describe frequent activation of allostatic systems.
Repeated hits from multiple stressors resulting in overexposure to stress hormones
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Describe lack of adaption to repeated stressor.
- Lack of adaption to the same stressor
- Ex. public speaking
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Describe failure to shut off allostatic activation after stress.
- Inability to efficiently shut off stress response resulting in overexposure to stress hormones
- Ex. Impaired negative feedback regulation of cort
- Hippocampus malfunction in aging
- Individual variability comes into play
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What does a normal physiological response to stress look like plotted?
Gradual rise and fall
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What does does the stress response for repeated "hits" look like plotted?
Normal response repeated over time, gradually decreasing in height
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What does the stress response for lack of adaption look like plotted?
Repeated peaks at the same height
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What does the plot look like for prolonged stress response?
- Increase
- Then plataeu with no recovery
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What does the plot for inadequate stress response look like?
Barely any increase and then a decrease back to baseline
-
What kind of allostasis does stress induce?
Either adaptive or maladaptive allostasis of stress mediators
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Stress mediators constitute what?
- ANS (blood pressure, catecholamines)
- Metabolic hormones (cortisol, insulin)
- Pro- & anti-inflammatory cytokines
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What happens if stress stimuli are excessive and repetitive?
- Recovery to the original homeostatic levels may be incomplete
- Chronic stress can make a body system think the stress of new enviroments would persist
- Demands newly defined set point for future adaption
- Diff btwn new and old set points called 'cumulative burden of adaptation to stress'
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What is the difference between new and old set points for stress mediators called?
Cumulative burden of adaptation to stress
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What's an example of cumulative burden of adaptation to stress?
Allostatic load
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Where can examples of allostatic load be found?
- Primary mediators
- Secondary outcomes
- Or tertiary outcomes
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What are examples of allostatic load in primary mediators?
- Hypercortisolemia
- Increased inflammatory cytokines
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What are examples of allostatic load in secondary outcomes?
- Elevated blood pressure
- Overweight
- Insulin resistance
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What are examples of allostatic load in tertiary outcomes?
- Hypertension
- Diabetes
- Obesity
- Coronary heart disease
- Neurodegenerative disorders
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What part of the physiology does the stress response affect- activation and overload?
- Immune suppression
- Reproductive distress
- Digestive tract
- Cardiovascular
- Bone
- Metabolism
- Accelerated aging
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What happens to the physiology of the digestive tract as a result of stress response activation and overload/wear and tear?
- Peptic ulcers
- Decreased nutrient absorption
- Stunted growth
- Colitis
- Irritable bowel syndrome
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What are examples of energy mobilization for gastro-intestinal tract during fight or flight response?
- GI shuts down
- No saliva production (dry mouth)
- No stomach mvmt, enzyme secretion, blood flow
- Small intestine suppressed, large intestine moves so no water re-absorption
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What happens to your cardiovascular system as a result of stress response activation and overload/wear and tear?
- Atheriolosclerosis
- Hypertension
- Chronic myocardial ischemia
- Sudden cardiac arrest
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What are examples of energy mobilization for cardiovascular system during fight or flight response?
- Increased sympathetic and decreased parasympathetic signaling
- Increased heart rate and cardiac output
- Increased blood pressure (vasoconstriction)
- Increased blood flow to brain and muscles
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WHat happens to your bones as a result of stress response activation and overload?
- Stunted growth
- Osteoporosis
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What happens to your metabolism as a result of stress response activation and overload/wear and tear?
- Inefficient process; fatigue
- GCs decrease insulin sensitivity in adipocytes, and exacerbate insulin resistance or glucose intolerance
- Late-onset Diabetes Type II, prediabetes
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What are examples of energy mobilization for metabolism during flight or fight response?
- Decreased insulin secretion
- GC block glucose transport to adipocytes, glycogenolysis, and protein breakdown
- All together- increased blood glucose levels
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The stress response is all about energy _________.
Mobilization
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What are some non-vital functions that are repressed during the response to stress?
- Reproduction
- Growth
- Digestion
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