Stress. What is stress? Acute physical stressors Acute physical stressors Zebras, lions… Zebras,...

StressStress

What is stress?What is stress?

Acute physical stressorsAcute physical stressors Zebras, lions…Zebras, lions…

Chronic physical stressorsChronic physical stressors Drought, famine, parasitesDrought, famine, parasites

Psychological and social stressorsPsychological and social stressors Relationships, debt, care for dying relativeRelationships, debt, care for dying relative

What is a stressor?What is a stressor?

Hans Selye: Anything that throws body Hans Selye: Anything that throws body out of allostatic balanceout of allostatic balance Allostasis: range of measures appropriate for Allostasis: range of measures appropriate for

situation (sleep vs. bungee-jumping)situation (sleep vs. bungee-jumping)

Heat, cold, illness, injury, hungerHeat, cold, illness, injury, hunger

Can include anticipation of eventCan include anticipation of event

Hans SelyeHans Selye

Early research project: Ovarian extract—Early research project: Ovarian extract—What does it do?What does it do? Inject rats every day Inject rats every day ulcers, enlarged ulcers, enlarged

adrenal glands, & shrunken immune tissuesadrenal glands, & shrunken immune tissues So did control rats!!So did control rats!! So did others subjected to cold, heat, forced So did others subjected to cold, heat, forced

exercise, surgical proceduresexercise, surgical procedures Stress!Stress!

15.17 Autonomic Activation during a Stress Situation (Part 1)

Why growth hormone???Why growth hormone???

Brief responseBrief response Increases mobilization of stored energyIncreases mobilization of stored energy

Can be used for growthCan be used for growth --or for exercising muscle--or for exercising muscle

Somatomedin (needed for growth) is Somatomedin (needed for growth) is suppressedsuppressed

Therefore, increased energy for musclesTherefore, increased energy for muscles

Selye: General Adaptation Selye: General Adaptation SyndromeSyndrome

Alarm stage: initial response (sympathetic NS)Alarm stage: initial response (sympathetic NS) Mobilize energy from stores, inhibit further storageMobilize energy from stores, inhibit further storage

Tornado = no time to repaint the kitchen (Sapolsky)Tornado = no time to repaint the kitchen (Sapolsky) Inhibit digestion, growth, reproduction, immunityInhibit digestion, growth, reproduction, immunity

Increase HR, BP, breathingIncrease HR, BP, breathing Walter Cannon: Fight or flight responseWalter Cannon: Fight or flight response AnalgesiaAnalgesia Aspects of senses and memory improveAspects of senses and memory improve


Resistance, or adaptation if stressor continuesResistance, or adaptation if stressor continues Increased cortisol (~ heating house by burning Increased cortisol (~ heating house by burning

furniture)furniture) Liver:Liver:

Gluconeogenesis: Amino acids, glycerol Gluconeogenesis: Amino acids, glycerol glucose glucose Glycogenolysis: Glycogen Glycogenolysis: Glycogen glucose glucose

Skeletal muscle:Skeletal muscle: Decrease protein synthesis, increase degradationDecrease protein synthesis, increase degradation Decrease glucose uptakeDecrease glucose uptake

Fat:Fat: Decrease glucose uptake; increase lipid mobilizationDecrease glucose uptake; increase lipid mobilization


Resistance (cont.)Resistance (cont.) CortisolCortisol

Anti-inflammatoryAnti-inflammatory Decrease vasodilation, capillary permeability, Decrease vasodilation, capillary permeability,

ImmunosuppressionImmunosuppression Decrease antibody productionDecrease antibody production Decrease circulating lymphocytesDecrease circulating lymphocytes


ExhaustionExhaustion Resources depleted (Penny-wise, dollar-Resources depleted (Penny-wise, dollar-

foolish)foolish) Never store extra energy; fatigue rapidly; Never store extra energy; fatigue rapidly;

increase chance of diabetesincrease chance of diabetes Increased blood pressure, heart disease, Increased blood pressure, heart disease,

strokesstrokes Reproductive disordersReproductive disorders Hippocampus neurons destroyedHippocampus neurons destroyed Immune suppressionImmune suppression

Effects of severe or prolonged Effects of severe or prolonged stress on memorystress on memory

GCs kill hippocampal neurons.GCs kill hippocampal neurons. (vicious circle: less inhibitory control of GCs)(vicious circle: less inhibitory control of GCs)

Dendrite and axon retraction.Dendrite and axon retraction. Inhibition of hippocampal neurogenesis.Inhibition of hippocampal neurogenesis. Long-term depression Long-term depression (opposite of long term (opposite of long term

potentiation, which is a basis for memory formation)potentiation, which is a basis for memory formation) Uses a different glutamate receptor: metabotropic Uses a different glutamate receptor: metabotropic

receptor (mGluR) & slow rates of stimulation.receptor (mGluR) & slow rates of stimulation. AMPA receptors are REMOVED from synapse.AMPA receptors are REMOVED from synapse.

Individual differencesIndividual differences

Sapolsky: baboons in KenyaSapolsky: baboons in Kenya Food abundant, predators rareFood abundant, predators rare Stressors = what they do to each otherStressors = what they do to each other Dominant male: T & cortisol levels recover fasterDominant male: T & cortisol levels recover faster Subordinate:Subordinate:

Resting glucocorticoids (GCs) are higher.Resting glucocorticoids (GCs) are higher. Real stressor: GC response = slower, lower, longerReal stressor: GC response = slower, lower, longer High BP, low HDL, fewer lymphocytes, High BP, low HDL, fewer lymphocytes,

low insulin-like growth factor (heals wounds)low insulin-like growth factor (heals wounds)

Individual differencesIndividual differences

Subordinate baboons = sick??? Too simplisticSubordinate baboons = sick??? Too simplistic Dominant males may fight to stay on top.Dominant males may fight to stay on top.

Elevated GCsElevated GCs If subordinates not harassed If subordinates not harassed not bad not bad Social support: groom females, play with kidsSocial support: groom females, play with kids Status rising or fallingStatus rising or falling Glass half full/half emptyGlass half full/half empty

Baboons grooming Baboons grooming

Michael MeaneyMichael Meaney

Early experienceEarly experience

Early handling Early handling better stress response later better stress response later

High licking & grooming dams ~ handlingHigh licking & grooming dams ~ handling

Genetic vs. environmental?Genetic vs. environmental?

M. MeaneyM. Meaney

Cross-fosterCross-foster Mostly the actual L&G, not geneticsMostly the actual L&G, not genetics

No diff in birth wts., weaning wts, or # of No diff in birth wts., weaning wts, or # of pupspups

HLG dams groomed 2 X as much as LLG HLG dams groomed 2 X as much as LLG dams, only in 1dams, only in 1stst wk wk

HLG pups: 2 X GC receptor proteins in HLG pups: 2 X GC receptor proteins in hippocampus; mineralocorticoid Rs hippocampus; mineralocorticoid Rs Neg. feedback on HPA axis.Neg. feedback on HPA axis.

Immune SystemImmune System

Innate immunityInnate immunity Skin, mucous membranesSkin, mucous membranes Cough, sneeze, vomit reflexesCough, sneeze, vomit reflexes Acidic pH of tissuesAcidic pH of tissues FeverFever Interferon Interferon MacrophagesMacrophages Microglia of CNSMicroglia of CNS

Immune systemImmune system

Acquired immunityAcquired immunity Late in evolution (vertebrates)Late in evolution (vertebrates) Capacity to respond; actual response only if Capacity to respond; actual response only if

prior experience w/ that invaderprior experience w/ that invader Edward Jenner (18Edward Jenner (18thth century): vaccinated boy century): vaccinated boy

w/ cow pox w/ cow pox didn’t catch small pox. didn’t catch small pox. Vaccination from “vacca” (Latin for cow)Vaccination from “vacca” (Latin for cow)

15.20 Main Components of the Human Immune System (Part 1)

Organs of immune systemOrgans of immune system

Lymphatic systemLymphatic system transport lymph: interstitial spaces to bloodtransport lymph: interstitial spaces to blood Lymph nodes: enlarged spaces where foreign Lymph nodes: enlarged spaces where foreign

substances are trapped & phagocytizedsubstances are trapped & phagocytized Spleen: upper left abdomenSpleen: upper left abdomen

Blood filter, storage for lymphocytesBlood filter, storage for lymphocytes Large phagocytic cells devour old red blood Large phagocytic cells devour old red blood

cells, bacteria, cell particles, toxinscells, bacteria, cell particles, toxins Antibodies made and released hereAntibodies made and released here

Organs of immune systemOrgans of immune system

Thymus: behind sternum (breast bone)Thymus: behind sternum (breast bone) Immature T cells mature here. 90% die Immature T cells mature here. 90% die

because they recognize “self” proteinsbecause they recognize “self” proteins Secretes hormones (thymosin & thymopoeitin) Secretes hormones (thymosin & thymopoeitin)

increse production of more T cells increse production of more T cells Bone marrow: stem cells divide to produce Bone marrow: stem cells divide to produce

immune system cellsimmune system cells

Lymph nodeLymph node

Major histocompatibility complex Major histocompatibility complex (MHC) proteins(MHC) proteins

Proteins on cell surface that define “self”Proteins on cell surface that define “self” MHC I: large polypeptide chains (300-450 MHC I: large polypeptide chains (300-450

a.a.’s), linked to Beta-2 microglobulin.a.a.’s), linked to Beta-2 microglobulin. On surface of most cellsOn surface of most cells

MHC II: 2 polypeptide chains (~200 a.a.s MHC II: 2 polypeptide chains (~200 a.a.s each) each) On B cells, T cells, macrophages, specialized On B cells, T cells, macrophages, specialized

epithelial cells: “police badge” of immune sys.epithelial cells: “police badge” of immune sys.

Cells of immune systemCells of immune system

Macrophages (literally, “big eaters”)Macrophages (literally, “big eaters”) Ingest invaders, display epitopes to T cellsIngest invaders, display epitopes to T cells

Epitope = smallest bit of antigen that can be recognized by Epitope = smallest bit of antigen that can be recognized by immune cellimmune cell

Can kill invader with large amount of nitric oxide (NO) Can kill invader with large amount of nitric oxide (NO) (via inducible NO synthase, iNOS)(via inducible NO synthase, iNOS)

Produce interleukin-1 (a cytokine) Produce interleukin-1 (a cytokine) activates T cells, activates T cells, which in turn produce interleukin-2, which attracts which in turn produce interleukin-2, which attracts macrophages & increases production of more T cellsmacrophages & increases production of more T cells

Produce B cell growth factorProduce B cell growth factor (Great oversimplification: 16 interleukins, interferon, (Great oversimplification: 16 interleukins, interferon,

other cytokines)other cytokines)

Macrophage (gray) approaching Macrophage (gray) approaching a chain of a chain of Streptococcus Streptococcus

pyogenespyogenes (yellow). On top of the (yellow). On top of the macrophage is a spherical macrophage is a spherical

lymphocyte.lymphocyte.

Cells of immune systemCells of immune system

B cells (originally from “bursa” in birds; B cells (originally from “bursa” in birds; mammals: B is for bone, where they mammals: B is for bone, where they mature)mature) Activated B cells become plasma cells, which Activated B cells become plasma cells, which

produce antibodies to invader’s epitopesproduce antibodies to invader’s epitopes Some remain as memory cells, ready for next Some remain as memory cells, ready for next

encounter w/ a similar invader. encounter w/ a similar invader.

AntibodiesAntibodies

Consist of 2 identical heavy polypeptide chains Consist of 2 identical heavy polypeptide chains (400-450 amino acids long) + 2 identical light (400-450 amino acids long) + 2 identical light chains (~200 a.a.’s long). Each heavy chain is chains (~200 a.a.’s long). Each heavy chain is attached to 1 light chain; heavy chains attach to attached to 1 light chain; heavy chains attach to each other each other Y-shaped structure Y-shaped structure

Forms 2 “claws” into which epitope fitsForms 2 “claws” into which epitope fits Variable region interacts w/ epitope (Each Ab Variable region interacts w/ epitope (Each Ab

can bind 2 epitopes, one on each prong.can bind 2 epitopes, one on each prong. Constant region confers specific functionConstant region confers specific function

Antibodies (cont.)Antibodies (cont.)

Functions of antibodies (Ab’s)Functions of antibodies (Ab’s) Agglutination: clumping of antigens (Ag’s) that are too Agglutination: clumping of antigens (Ag’s) that are too

small for macrophage to detectsmall for macrophage to detect Precipitation: Ab binds to soluble Ag, so it can’t enter Precipitation: Ab binds to soluble Ag, so it can’t enter

cellcell Opsonization (to “make appetizing”): Ab binds to Opsonization (to “make appetizing”): Ab binds to

slippery film on surface of microorganism, so slippery film on surface of microorganism, so macrophage can catch & eat itmacrophage can catch & eat it

Neutralization: Ab binds to toxinNeutralization: Ab binds to toxin neutralizes neutralizes Lysis: Ab+Ag exposes area on Ab that binds to Lysis: Ab+Ag exposes area on Ab that binds to

complement protein in bloodcomplement protein in bloodlesions in invader’s cell lesions in invader’s cell membranemembrane

Antibodies (cont.)Antibodies (cont.)

Problem: Each individual can make 1 M to 1 B Problem: Each individual can make 1 M to 1 B different antibodies; each requires a complex different antibodies; each requires a complex genetic code. Not enough genes!genetic code. Not enough genes! Introduce variability by:Introduce variability by: Genetic rearrangement: light & heavy chains coded Genetic rearrangement: light & heavy chains coded

on different chromosomes (~ Chinese menu: 2 from on different chromosomes (~ Chinese menu: 2 from column A, 3 from column B)column A, 3 from column B)

Genetic “mistakes” in making Ab’s (deliberately & with Genetic “mistakes” in making Ab’s (deliberately & with a vengeance)a vengeance)

B cell mutations: Activation by epitope that doesn’t fit B cell mutations: Activation by epitope that doesn’t fit exactlyexactlyproliferation w/ “errors”, some of which fit proliferation w/ “errors”, some of which fit better than original: ~ evolutionbetter than original: ~ evolution

Immune system cellsImmune system cells

T cells T cells Mature in thymus (hence their name)Mature in thymus (hence their name) Cytotoxic T cells (CD8+) kill infected self cellsCytotoxic T cells (CD8+) kill infected self cells Helper T cells (CD4+) activate B & CD8+ cellsHelper T cells (CD4+) activate B & CD8+ cells Suppressor T cells: suppress immune Suppressor T cells: suppress immune

response after infection is overresponse after infection is over Recognize antigen only if it is presented in Recognize antigen only if it is presented in

combination with MHC protein on another cellcombination with MHC protein on another cell


Helper T cells (CD4+)Helper T cells (CD4+) Recognize MHC II molecules + antigenRecognize MHC II molecules + antigen

MHC II molecules actually hold the antigenMHC II molecules actually hold the antigen Activate resting B cells Activate resting B cells plasma cells that plasma cells that

secrete Ab’s.secrete Ab’s. Also produce interleukin 2Also produce interleukin 2

attracts macrophagesattracts macrophages proliferation of T cellsproliferation of T cells


Cytotoxic T cells (CD8+)Cytotoxic T cells (CD8+) Recognize MHC I “self” molecules + portions Recognize MHC I “self” molecules + portions

of antigen on cell surface.of antigen on cell surface. Kills cells by injecting something that forms Kills cells by injecting something that forms

pores in membrane pores in membrane lysis lysis Don’t attack bacteria: No MHC I moleculeDon’t attack bacteria: No MHC I molecule Don’t attack normal “self” cells: no foreign Don’t attack normal “self” cells: no foreign

antigenantigen Function: Kill cells taken over by virusFunction: Kill cells taken over by virus

Stress and immunityStress and immunity Sapolsky: The brain has a vast potential for Sapolsky: The brain has a vast potential for

sticking its nose in the immune system’s sticking its nose in the immune system’s business.business.

GC’s shrink thymus GC’s shrink thymus Inhibit release of interleukins & interferonsInhibit release of interleukins & interferons

Lymphocytes less responsive to invadersLymphocytes less responsive to invaders Return circulating lymphocytes to storage or Return circulating lymphocytes to storage or

“front lines.”“front lines.” Kill older lymphocytes (induce apoptosis)Kill older lymphocytes (induce apoptosis) Symp. N.S., beta-endorphin, CRH also inhibit in Symp. N.S., beta-endorphin, CRH also inhibit in

various waysvarious ways

Stress and immunityStress and immunity

With short duration stressors, there is With short duration stressors, there is actually an increase in immune response.actually an increase in immune response. Downturn after initial 30’ rise: due to sculpting Downturn after initial 30’ rise: due to sculpting

(removing older, less functional immune cells)(removing older, less functional immune cells) Sometimes autoimmune disease is worse with Sometimes autoimmune disease is worse with

lengthy stressors: may be due to repeated lengthy stressors: may be due to repeated early phase increases.early phase increases.


Why isn’t the link between chronic stress Why isn’t the link between chronic stress and illness stronger?and illness stronger? Variable severity of stressors & perception of Variable severity of stressors & perception of

stressfulnessstressfulness Moderate increases stimulate immune systemModerate increases stimulate immune system Minor fluctuations may not be critical.Minor fluctuations may not be critical. Scientists don’t deliberately make us sick.Scientists don’t deliberately make us sick.


Social isolation and longevitySocial isolation and longevity

Social relationships as important a factor as Social relationships as important a factor as smoking, obesity, inactivity, hypertension.smoking, obesity, inactivity, hypertension.

Not just due to altered risk factors (taking Not just due to altered risk factors (taking better care of themselves)better care of themselves) Same effect in monkeys in controlled conditionsSame effect in monkeys in controlled conditions


People rated how stressed they felt; then were People rated how stressed they felt; then were exposed to rhinovirusexposed to rhinovirus More stress More stress more colds more colds Same finding with monkeysSame finding with monkeys

CancerCancer Rats: controllable stress Rats: controllable stress no effect no effect

Uncontrollable stress Uncontrollable stress more virus-caused cancer more virus-caused cancer

Humans: little link with cancer onset, but optimism, Humans: little link with cancer onset, but optimism, assertiveness, social support can extend life in those assertiveness, social support can extend life in those who already have cancer.who already have cancer.

Stress and healthStress and health

Long-term uncontrollable stress Long-term uncontrollable stress Inhibits immune systemInhibits immune system Depletes energy stores Depletes energy stores always tired always tired Kills neurons in hippocampusKills neurons in hippocampus

Interferes with memoryInterferes with memory Increases depressionIncreases depression Antidepressants Antidepressants hippocampal neurogenesis as hippocampal neurogenesis as

they improve mood.they improve mood. Glucocorticoid antagonists can be used to treat Glucocorticoid antagonists can be used to treat

depressiondepression

Stress and healthStress and health

Controllable stressControllable stress May be more beneficial than no stress at allMay be more beneficial than no stress at all

Many people thrive on challenge.Many people thrive on challenge.

Prefrontal cortex evaluates controllability and Prefrontal cortex evaluates controllability and inhibits stress responses.inhibits stress responses.

Brief high GC levels facilitate coping and Brief high GC levels facilitate coping and increase memory (stimulate hippocampus).increase memory (stimulate hippocampus).

Amat et al., 2005, Amat et al., 2005, (Nat. Ns. 8:365-71)(Nat. Ns. 8:365-71)

Inescapable stress (IS) Inescapable stress (IS) inability to learn inability to learn later escapable stress (ES) ES and later escapable stress (ES) ES and increases freezing in stress situation.increases freezing in stress situation.

IS IS more activation (Fos) & 5-HT release more activation (Fos) & 5-HT release from caudal DRN neurons than escapable from caudal DRN neurons than escapable stress (ES). (also more NE from locus stress (ES). (also more NE from locus coeruleus)coeruleus)

Block activity in mPFCv Block activity in mPFCv w/w/ muscimol muscimol (GABA(GABAAA agonist agonist)): : ES as bad as IS. ES as bad as IS.

Amat et al., 2005, Amat et al., 2005, (Nat. Ns. 8:365-(Nat. Ns. 8:365-71) (cont.)71) (cont.)

Effect of muscimol in mPFCv was site-specific.Effect of muscimol in mPFCv was site-specific. Injections 2 mm anterior or posterior were ineffective.Injections 2 mm anterior or posterior were ineffective.

Inactivation of mPFCv did not impair ability to Inactivation of mPFCv did not impair ability to learn the initial wheel-turn escape response—learn the initial wheel-turn escape response—only the shuttle escape response after the only the shuttle escape response after the previous IS.previous IS.

Therefore, mPFCv mediates the calming effect Therefore, mPFCv mediates the calming effect of escapable stress.of escapable stress.

Robbins, 2005, Robbins, 2005, (Nat. Ns. 8:261-2)(Nat. Ns. 8:261-2)

mPFC is important for detecting mPFC is important for detecting controllability: tells DRN to “cool it.” controllability: tells DRN to “cool it.”

mPFC may indirectly affect other systems, mPFC may indirectly affect other systems, including noradrenergic, dopaminergic, & including noradrenergic, dopaminergic, & cholinergic.cholinergic. Midbrain DA system: error detection in reward Midbrain DA system: error detection in reward

learning.learning.

Main IdeasMain Ideas

1.1. Stress increases sympathetic Stress increases sympathetic responses: heart rate, blood pressure.responses: heart rate, blood pressure.

2. Glucocorticoids (GCs) mobilize glucose.2. Glucocorticoids (GCs) mobilize glucose.

3. Long-term stress inhibits immune sys., 3. Long-term stress inhibits immune sys., can can high blood pressure, heart disease high blood pressure, heart disease


4. Immune system: 4. Immune system: B-cells B-cells antibodies, remain as memory cells antibodies, remain as memory cells

Antibodies bind to epitope of invader and Antibodies bind to epitope of invader and assist in removal of invaderassist in removal of invader

T-cells: T-cells: Killer Killer Kills infected self cells Kills infected self cells Helper Helper activates other immune cells activates other immune cells Suppressor Suppressor shuts down response after shuts down response after

invader is goneinvader is gone Natural killer cells: can kill a variety of infected Natural killer cells: can kill a variety of infected

cellscells


5.5. Controllable stress can be good.Controllable stress can be good. Increases immune responseIncreases immune response Increases memoryIncreases memory mPFC mediates the calming effect of mPFC mediates the calming effect of

controllable stress.controllable stress. 6.6. Individual differences: Individual differences:

Perception of stress (half empty/half full)Perception of stress (half empty/half full) Social supportSocial support Early handlingEarly handling

Stress. What is stress? Acute physical stressors Acute physical stressors Zebras, lions… Zebras,...

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Transcript of Stress. What is stress? Acute physical stressors Acute physical stressors Zebras, lions… Zebras,...