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
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
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
What happens when there's a high amount of estrogen in the hippocampus?
High estrogen protects the hippocampus
How does high estrogen protect the hippocampus?
- Increases neuronal survival of necrotic insult
- Enhances dendritic sprouting and synapse formation
- Strengthens Long Term Potentiation (LTP)
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
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
How would you get certain engineered proteins into brain cells?
- New genetic material
- Use either virus or stem cells
- Inject into brain
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
What is the normal fight or flight stress response pathway?
- Stressful signal
- HPA axis
- Increases heart rate, blood pressure, and blood flow to muscles
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)
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
Describe the roadmap to neuroanatomy.
What is the autonomic nervous system (ANS)?
- Division of the peripheral nervous system
- Influences the function of internal organs
What are some of organ functions that the ANS influences?
- Heart rate
- Respiratory rate
- Pupillary response
What are the 2 divisions of the ANS?
What is the parasympathetic division generally responsible for?
Rest and digest
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
What is the sympathetic division generally responsible for?
Fight or flight
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
What hormones does the adrenal medulla release?
- Adrenaline (aka epinephrine)
- Noradrenaline (aka norepinephrine)
Which amino acid are adrenaline and noradrenaline derived from?
What is the splanchnic nerve?
Neurons that are part of the sympathetic branch of the nervous system
The adrenal medulla is innervated by which nerve/set of neurons?
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
What do the hormones adrenaline and noradrenaline bind to in the blood?
- Adrenergic hormones
- Transmembrane proteins in the plasma membrane of many cell types
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
Associated nerves and prevertebral ganglia send out what kind of fibers?
Associated nerves and terminal ganglia send out what kind of fibers?
What are chromaffin cells?
- Neuroendocrine cells in the adrenal medulla
- Release adrenaline and noradrenaline in response to neural input
The binding of a catecholamine to an adrenergic receptor will generally stimulate which nervous system?
Sympathetic nervous system
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
What is the longer pathway for the fight or flight stress response?
- Stress signal
- 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
Adrenaline and NE effects are immediate, and ___________?
What is allostasis?
- Maintianing stability (or homeostasis) through change
- The process of achieving stability, or homeostasis, through physiological or behavioral change
When does an allostatic sttate occur?
When set-points vary outside homeostatic limits and results in an imbalance of the primary mediators
How can allostasis be carried out?
- By means of alteration in:
- HPA axis hormones
- The autonomic nervous system
- Or a number of other systems
Allostasis is generally adaptive in the ____-term.
Why is allostasis essential?
In order to maintain internal viability amid changing conditions
Who made the term allostatic load?
McEwen and Stellar (1993)
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
What is homeostasis?
The regulation of the body to a balance, by single point tuning
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
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
What is allostatic overload?
Pathological condition that could develop
Every system in the body responds to acte challenge with what?
What results from acute challenges becoming chronic?
What's the point of allostatic load resulting from acute challenges turning chronic?
- Nothing, serves no useful purpose
- Just predisposes individuals to disease (overload)
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
Describe frequent activation of allostatic systems.
Repeated hits from multiple stressors resulting in overexposure to stress hormones
Describe lack of adaption to repeated stressor.
- Lack of adaption to the same stressor
- Ex. public speaking
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
What does a normal physiological response to stress look like plotted?
Gradual rise and fall
What does does the stress response for repeated "hits" look like plotted?
Normal response repeated over time, gradually decreasing in height
What does the stress response for lack of adaption look like plotted?
Repeated peaks at the same height
What does the plot look like for prolonged stress response?
- Then plataeu with no recovery
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
Stress mediators constitute what?
- ANS (blood pressure, catecholamines)
- Metabolic hormones (cortisol, insulin)
- Pro- & anti-inflammatory cytokines
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'
What is the difference between new and old set points for stress mediators called?
Cumulative burden of adaptation to stress
What's an example of cumulative burden of adaptation to stress?
Where can examples of allostatic load be found?
- Primary mediators
- Secondary outcomes
- Or tertiary outcomes
What are examples of allostatic load in primary mediators?
- Increased inflammatory cytokines
What are examples of allostatic load in secondary outcomes?
- Elevated blood pressure
- Insulin resistance
What are examples of allostatic load in tertiary outcomes?
- Coronary heart disease
- Neurodegenerative disorders
What part of the physiology does the stress response affect- activation and overload?
- Immune suppression
- Reproductive distress
- Digestive tract
- Accelerated aging
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
- Irritable bowel syndrome
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
What happens to your cardiovascular system as a result of stress response activation and overload/wear and tear?
- Chronic myocardial ischemia
- Sudden cardiac arrest
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
WHat happens to your bones as a result of stress response activation and overload?
- Stunted growth
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
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
The stress response is all about energy _________.
What are some non-vital functions that are repressed during the response to stress?