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Stress - growth - develoment
- 1. STRESS AND HUMAN GROWTH AND DEVELOPMENT George P. Chrousos University of Athens
- 2. Stress in Early Life • Stress and Development Concepts • Stress Mechanisms • Effects of the Stress System on the Developing Organism
- 3. “From the child of five to myself is but a step. But from the newborn baby to the child of five is an appalling distance” Leon Tolstoy 19th century
- 4. Ηβη, Hebe Puberty vs. Adolescence Ενήβωση vs. Εφηβεία Ephebiatrics
- 5. Puberty vs. Adolescence 12-15 y 12- >>15 y Ενήβωση vs. Εφηβεία
- 6. HUMAN COMPLEXITY: POSTGENOMIC ERA Human genome: About 3 billion bases About 20 thousand protein-coding genes About 18 thousand non coding RNA genes About 100-140 thousand transcripts (mRNA, ncRNA, miRNAs) About 200-260 thousand proteins Single nucleotide polymorphisms (snp’s), microsatellites or copy number variants (cnv’s): About 23 million snp’s About 20 million microsatellites >700 cnv’s (many million bases) 60% of genes have GPC islands Over 10 k disease-related mutations
- 7. HUMAN COMPLEXITY: SOME HUMAN BRAIN NUMBERS ~ 100 billion neurons (100x1012) x >10.000 synapses per neuron (>1018 synapses) ~ 100.000 km of fibers ~ 1 trillion or more glial cells ~ 1.25 terabytes ~ 15 Watt lamp (20% energy, 2% of weight)
- 8. The Human Brain • Plato (Meno) The innate preformation theory (Genetic view) • Aristotle The blank state theory (Epigenetic view)
- 11. A. THE DEVELOPING BRAIN Birth 2y Puberty Adulthood No.ofsynapses/2-Deoxyglucoseuptake Pruning / Neuronal Darwinism
- 12. Cognitive and Language Development
- 16. Ερεθίσματα και Εγκέφαλος "Use it or lose it" The brain loses the nervous circuits that are not used !
- 18. G.P. Chrousos 18
- 19. Functional Networks Fair et al. PLOs 2009
- 20. The Stream of Consciousness Default Mode Network 50% of resting brain energy ADULT: PFC, cingulate c, parietal c NEWBORN: Visual cortex
- 21. Default Network Fair et al. PNAS 2008
- 22. Brain plasticity research suggests that experience can change neural patterns, for better or for worse.
- 23. Focal Point: Prefrontal Deficits • Compromises the ability to interpret social cues during interpersonal interactions • Leads to misperceptions of threat or hostility in conflict situations • Permits negative affect states and other maladaptive responses to dominate • Heightened sensitivity to rewards • Impulsivity and inattention • Insensitivity to consequences Frontal lobes Gray matter volume peaks ~ age 12Gray matter volume peaks ~ age 12 Change with experience =Change with experience = plasticityplasticity Memory, planning, problem solvingMemory, planning, problem solving
- 24. Humans as Complex Biological Systems • Organism • Society “Resonance”, “mirror” and “spindle” (von Economo) neurons “Emotional Epidemiology”
- 25. Phenomenology of empathy Edith Stein (1891-1942). On the Problem of Empathy (1916). Edmund Husserl (1859-1938).
- 26. Charles Darwin, The Descent of Man “ any animal whatever, endowed with well marked social instincts, the parental and filial affections here included, would inevitably acquire a moral sense or conscience, as soon as its intellectual powers had become as well, or nearly as well developed, as in Man”
- 27. Frans de Waal, Ann Rev Psychol 2008 Putting the Altruism back into Altruism: The Evolution of Empathy “Moral instincts had their beginnings in circuits of emotional contagion or empathy”
- 28. Ethical engagement “Aid to others in need would never be internalized as a duty without the fellow- feeling that drives people to take an interest in one another. Moral sentiments came first; moral principles second.” -- Frans de Waal, 1996, p. 87. Cf. Mengzi (Mencius), Hume, Adam Smith, and HH the Dalai
- 29. Stress in Early Life Growth: Stature, Body weight, Body composition, Body shape, Puberty Development: Adjustment, Psychopathology Concurrent and/or Adult Pathology
- 30. Vulnerability of Developing Organisms • Development/Tissue formation • Increased metabolic rate • Decreased DNA repair • Decreased liver metabolism/xenobiotics • Decreased immune function • Decreased BBB • Programming
- 31. Pythagoras 6th century BCE
- 32. Disturbing Forces Harmony Equilibrium Balance Counteracting Reestablishing Forces IIIIII Stressors Homeostasis Adaptive Response (Physical, Emotional) Pythagoras= Harmony Alcmaeon=Iso-nomia Walter Cannon= Homeostasis
- 33. Load=Stressor Elastic region Deformation=Adaptive response Plastic region Yield point=Tipping point Fracture point (Death) Hooke’s Law (Load deformation curve) Eustress, Homeostasis, Eustasis Distress, Dyshomeostasis =Allostasis=Cacostasis
- 34. Homeostasis over Time Healthy Baseline Homeostasis Baseline Homeostasis=Eustasis Deteriorated Homeostasis=Cacostasis Improved Homeostasis=Hyperstasis Distress
- 35. Homeostasis over Time Healthy Baseline Homeostasis = Eustasis Deteriorated Homeostasis = Cacostasis Improved Homeostasis = Hyperstasis
- 36. Human Stressors Daily hustles Life transitions Natural and unnatural catastrophies Starvation, Excessive nutrition, Excessive exercise Chronic disease Socioeconomic status (Dignity, minorities) Job loss, Downsizing, Loss of control Bereavement/Caretaking (Pathologic empathy) Addictions/ Toxic substances Inflammations (Traumatic, Infectious, Autoimmune, Allergic) Anxiety, Depression, Personality disorder Luck of sleep, Excessive sllep
- 37. Stressors in Developing Humans Intrauterine stress Early life stress: Lack or loss of caregiver support (Attachment, Bonding, Neglect, Abuse), trauma, puberty
- 38. HOMEOSTATIC SYSTEMS • Amygdala (Fear/Anger) • MCLS (Reward) • Stress - CRH/LC-NE • Cardiorespiratory • Metabolic • Immune • Fatigue - Pain • Sleep • Biologic clock
- 39. Deficiency Optimum Excess HomeostaticEffect Homeostatic System Activity Eustasis Allostasis Caco- Allostasis Caco-
- 40. ALLOSTASIS LOW HOMEOSTATIC SYSTEM ALLOSTASIS HIGH No Behavioral Inhibition Depression Hypoarousal Hypotension Insulin Resistance TH2 Auto-immune Disease, TH1 Infectious Disease Fatigue, Hyperalgesia Sleep Disturbances (Somnolence, Awakenings) Fear/Anger Reward Stress -CRH/LC-NE Cardiorespiratory Metabolic Immune Fatigue-Pain Sleep Behavioral Inhibition Depression Hyperarousal Hypertension Insulin Resistance TH1 Auto-immune Disease, TH2 Infectious disease Fatigue, Hyperalgesia Sleep Disturbances (Insomnia, Awakenings) HOMEOSTATIC SYSTEMS CHRONIC FUNCTIONING/DYSFUNCTIONING
- 41. “CRITICAL” PERIODS OF LIFE Prenatal, Early Childhood, Puberty Organizational Effects of Hormones (Stress, sex and immune hormones)
- 42. Stress in Early Life • Stress and Development Concepts • Stress Mechanisms • Effects of the Stress System on the Developing Organism
- 43. What Mediates the Adaptive Response? The Stress System a. CNS 1. CRH system 2. Locus caeruleus (LC)-norepinephrine (NE)/autonomic (sympathetic) systems b. Periphery 1. HPA axis 2. Autonomic (sympathetic) systems
- 45. EFFECTS OF I.C.V. CRH -Metabolic – activation of hypothalamic – pituitary – adrenal axis -Cardiovascular – activation of sympathetic nervous system -Immune- anti-inflammation, immunosuppression -Behavioral - decreased feeding - decreased sexual activity - assumption of freeze posture - irritability - activation
- 46. GH/IGF-1 LH/T TSH/T3 F NE/E iCRH IL-6 STRESS SYSTEM Amygdala CRH HIPPOCAMPUS CRH/AVP LC/NE ACTH Inflammation Sickness syndrome
- 47. Acute Stress MCLS AMYGDALA CRH PVN CRH/AVP LC/NE + + + + - - HIPPO- CAMPUS Cortisol Catecholamines/IL-6 Behavioral adaptation Physical adaptation
- 48. Immune Function CRH ACTH Glucocorticoids Target Tissues Mediators of (Eicosanoids, PAF, Serotonin) Inflammation (IL-1, IL-6, TNF) Cytokines CRH TRH ACTH Glucocorticoids TSH T4 Target Tissues T3 Target Tissues GHRH GH SmC STSSTS Growth and Thyroid Function CRHLHRH ACTH Glucocorticoids LH, FSH Target Tissues Reproduction -endorphin Testosterone, Estradiol
- 49. Regulated genes Metabolism DNA/RNA/Protein synthesis Cell development Miscellaneous ESTs Immune Response Clusters Number of Genes Down-regulated Number of Genes Up-regulated 5001000 1000500
- 51. Cellular Stress Inflammatory NF-kB NFAT5 Nutritional IR Oxidative Mitochondria Keap1 (SH sensor)-Nrf2-ΑRΕ
- 52. Stress in Early Life • Stress Concepts • Stress Mechanisms • Effects of the Stress System on the Developing Organism
- 53. Stress and Development Early Effects of Stress: •Infertility •Miscarriage •Premature Labor •Perinatal Death •Intrauterine Growth Retardation •Pre-metabolic Syndrome Changes •CNS Pre-behavioral Programming Changes
- 54. Stress and Development Later Effects of Stress : •Obesity •Metabolic Syndrome •Early Adrenarche, Puberty •Polycystic Ovary Syndrome •Osteoporosis •Behavioral/Psychosomatic Disorders
- 55. STRESS SYSTEM ACTIVITY Low Range “Normal” Range High Range Handling Natural Maternal Separation Percentsubjects
- 56. CRH Progressively Increases with Repeated Separation Stress of Infant Macaques PR: Peer-Reared MR: Mother-Reared
- 59. Systolic and Diastolic Blood Pressure-SDS * p=<0.001 * p=<0.001 *
- 60. Systolic Blood Pressure Comparison between SGA-IVF, AGA-IVF and controls
- 61. Triglycerides Comparison between IVF and controls
- 62. PREGNANCY FETUS Increased Nutrition, Gestational diabetes Decreased Nutrition, Stress Insulin IGF-1 Cortisol Catecholamines LGASGA Visceral Adiposity Metabolic Syndrome
- 63. Acute Stress MCLS AMYGDALA CRH PVN CRH/AVP LC/NE + + + + - - HIPPO- CAMPUS Cortisol Catecholamines/IL-6 Stress Hyper-responsive Child/Adult MCLS AMYGDALA CRH PVN CRH/AVP LC/NE - + + + - - HIPPO- CAMPUS Cortisol Catecholamines/IL-6 Somatic consequences Growth retardation Metabolic syndrome X Sickness syndrome Cardiovascular disease Osteoporosis Behavioral consequences Maladjustment disorders Anxiety, Depression Personality disorders Addiction, Psychosomatics Pain and fatigue syndromes + Adjusment vs. Maladjustment
- 64. GENETIC VARIATION DEVELOPMENTAL HISTORY STRESS Real or perceived HPA axis Endothelial Dysfunction/Inflammation Atherosclerosis Cardiovascular Disease Insulin resistance Visceral Obesity=Metabolic Syndrome Sarcopenia DM type 2 TG LDL HDL ABP APR Cytokines Stress system CRH/AVP-LC/NE GH/IGF-1 LH, T, E2 TSH, T3 Cortisol NE, E, IL-6Target Tissues Systemic Sympathetic Adrenomedullary Systems Dyscoagulation AGING NUTRITION Osteoporosis Sleep Apnea Sickness Syndrome PCOS
- 65. 0 2 4 6 8 10 12 20 30 40 50 60 IL-6(pg/ml) r = .790 p = .000 0 1 2 3 4 5 20 30 40 50 60 TNFa(pg/ml) r = .400 p = .014 BMI Both IL-6 and TNFa correlate with BMI JCEM 1997
- 68. Cushing Syndrome Pseudocushing Syndrome Chronic Stress Chronic Active Alcoholism Melancholic Depression Metabolic Syndrome (subgroup) “Benign” Premature Adrenarche Post Long Periods of Stress Linkage Studies with the GR AIDS-related insulin resistance/lipodystrophy Monkey Studies Seasonal Depression Atypical Depression THE STRESS SYSTEM AND THE METABOLIC SYNDROME
- 69. 24 H SAMPLING OVERNIGHT DEXAMETHASONE TEST A. B. PLASMACORTISOL 8 am 8 pm 8 am TARGET TISSUE SENSITIVITY TARGETTISSUERESPONSE CORTISOL CONCENTRATION HS N R THRESHOLD FOR HARMFULNESS -D -D +D +D NS CS NS CS 24HCORTISOL DARK Chrousos, IJO 1998
- 70. Circadian Rhythm Transcription Factor CLOCK/BMAL1 Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Acetylation Nancy Nader1 George P. Chrousos2 and Tomoshige Kino1 1: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA 2: First Department of Pediatrics, Athens University Medical School, Athens 11527, Greece FASEB J 2009
- 71. Uncoupling between Circadian Rhythm of Circulating Cortisol and Tissue Glucocorticoid Sensitivity Produces Pathology 8 am 8 pm 8 amDark TargetTissue GlucocorticoidAction CIRCADIAN TISSUE GLUCOCORTICOID ACTION OVERNIGHT DEXAMETHASONE TESTPlasmaCortisol -D -D +D +D NS SS8 am 8 pm 8 amDark 24 H SAMPLING Normal Stress Shift
- 72. DEPRESSION visceral fat cortisol catecholamines Melancholic Atypical Metabolic Syndrome visceral fat lean body mass bone mass cortisol catecholamines insulin
- 73. Post Long Periods of Stress Neoplasia Rx Anorexia Nervosa Malnutrition Extreme Athleticism Dependencies THE STRESS SYSTEM AND THE METABOLIC SYNDROME
- 74. 74
- 75. Selections of Genetic and Epigenetic Networks Participating in Functions Important for Human Survival and Species Preservation RESPONSE TO SURVIVAL THREAT SELECTIVE ADVANTAGE CONTEMPORARY DISEASE Combat starvation Energy conservation Obesity Combat dehydration Fluid and electrolyte conservation Hypertension Combat infectious diseases Potent immune reaction Autoimmunity/Allergy Anticipate adversaries Arousal/fear Anxiety/insomnia Minimize exposure to danger Withdrawal Depression Prevent tissue strain/damage Retain tissue integrity Pain and fatigue syndromes Chrousos, Amer J Med 2004
- 76. IndividualSpecies vs. Epigenotype Evolution Genetics CNS complexity Development Epigenetics CNS plasticity ENVIRONMENTAL STRESSORS Genotype Starvation Dehydration Injurious agents-inflammations Adversaries-anticipation Adversaries-avoidance Injury-minimization Phenotype Maternal Stress
- 77. DNA variation Histone modification Phenotype DNA methylation Protein CH3 HDAC MeCP2 NCoR Recruitment of HDACs & corepressors Binding of methyl-CpG binding proteins GENETIC MACHINERYENVIRONMENTAL TRIGGERS Smoking Exercise Toxins Diet Infection Stress Cold Heat Drugs
- 79. G.P. Chrousos 79
- 80. The first generation that will die younger than their parents
- 82. Finding Molecules that Potentially Alter GR Action Yeast Two-hybrid Screening Using GR Fragments as Baits
- 83. Yeast Two-hybrid Screening Using GR LBD as Bait 1 777 AF1 Immunogenic Domain DBD LBD 77 262 420 480 Bait Fragment Human GR LexA System/Human Jurkat Cell cDNA Library CLOCK transcription factor
- 84. CLOCK/BMAL1 Represses GR-induced Transcriptional Activity through Acetylation GREs GR GR-induced Transcriptional Activity In the Absence of Acetylation by CLOCK BMAL1 CLOCK Acetylation GRE Binding GREs A A A A In the Presence of Acetylation by CLOCK GR-induced Transcriptional Activity HRNTD DBD LBD GR Acetylation Sites Interaction with CLOCK K480 K492 K494 K495 1 420 480 520 777
- 85. Major, Recurrent Environmental Changes on the Earth Day/Night Changes (Recurrent Stress) Seasonal Changes Rotation of the Earth: Revolution of the Earth:
- 86. Kino T NICHD/NIH Adaptation to Day/Night Changes Day Exercise, Work, Food Intake and Other Activities: High Night Rest and Sleep Activities: Low Adjustment of internal homeostasis and synchronization of physical activities to Day/Night changes
- 87. Circadian Fluctuation of Plasma Cortisol 24 hr Plasma Cortisol Sampling PlasmaCortisol 8 am 8 pm 8 am Dark HPA Axis How does glucocorticoid action fluctuate in target tissues? Cortisol (-) (-) CRH/AVP ACTH Paraventricular Nucleus (PVN) Pituitary Gland Adrenal Gland Surachiasmatic Nucleus (SCN)
- 88. • 10-15 % of the mammalian transcriptome oscillates with a 24 h rhythm. • CLOCK System-controlled genes and downstream output genes are involved.
- 89. Nader, Chrousos, Kino, TEM 2010
- 90. Kino T NICHD/NIH CLOCK-mediated Gene-specific Regulation of Glucocorticoid Action at Peripheral Tissues PlasmaCortisol 8 am 8 pm Dark 8 am 8 pm Dark TargetTissue GlucocorticoidAction CIRCADIAN TISSUE GLUCOCORTICOID ACTION 24 hr SAMPLING 8 am 8 am Gene- (and Tissue-) specific Changes of Glucocorticoid- Responsive Genes (Transactivation/transrepressi on)
- 91. Loss of Circadian Rhythm and Glucocorticoid Excess Cause Similar Metabolic Disturbances Signs & Symptoms Loss of Circadian Rhythm Glucocorticoid Excess Glucose Metabolism Hyperglycemia Insulin Resistance Fat Metabolism Hyperlipidemia Fatty Liver Central Obesity Hypertension Appetite ++ ++ ++ ++ ++ + ++ ++ ++ ++ Nader, Chrousos, Kino, TEM 2010
- 92. Examples of pathology due to aberrant coupling of the CLOCK and HPA axis: -Chronic stress, evening F elevations -Endogenous/exogenous Cushing s. -Trans-time-zone travel -Nightshift work All above conditions are associated with a high risk for CVD
- 93. The developmental trajectories through adolescence and into adulthood Birth Childhood Puberty Early adulthood Developmental Stage Developmentalcourse Hormonal activational and organizational effects on brain and behavior Continuity in adjustment Transient adolescent maladjustment Adolescent maladjustment leading to adult psychiatric disorder
- 94. Internalizationsymptoms Chronological age Hayward et al., JAACAP, 1997 Nottelmann et al., J. Peds, 1987 Internalizationsymptoms Chronological age Early maturers Late maturers Early maturers Late maturers
- 95. Συμπάσχει η ψυχή τω σώματι νοσούντι και τεμνομένω, το δε σώμα τη ψυχή The soul suffers when the body is diseased or traumatized, while the body suffers when the soul is ailing Aristotle
- 96. Life on the Earth In addition to fighting against unforseen random stressors…. Organisms have adapted to recurrent environmental changes associated with the rotation of the earth.
- 97. • Emotional “comfort” eating, lack of sleep, impulsive behaviors and selection of specific foods often characterize stressed individuals. .
- 98. • Obese children and adolescents are frequently entangled in a vicious cycle between distress impairing self-image and distorted self-image maintaining and worsening distress.
- 100. Anxiety/Depression Metabolic s. / DM T2/ Sleep Apnea/PCOS CVD, Cancer Other Obesity Stress Inflammation
- 101. “From the child of five to myself is but a step. But from the newborn baby to the child of five is an appalling distance” Leon Tolstoy 19th century
- 105. Prevalence of BMI≥85th and ≥ 95th Percentile of 15 y of Age: Consensus Statement, 2004 Speiser, 2005
- 106. BMI curves, 2001 Boys Girls
- 107. BMI Curves in Relation to BMI 25 or 30 Boys Girls
- 108. A self-specifying (autonomous) system in dynamic coupling with its milieu.
- 109. 1. Form a thermodynamically open network. 2. Have organizational closure 3. Generate and sustain a relational identity under precarious conditions. 4. Bring forth a meaningful environment. A system is self-specifying (autonomous) when its constituent processes:
- 110. (1) Sensorimotor coupling • Imitation, sensorimotor matching.
- 111. (1) Sensorimotor coupling • Emotion sharing, affective resonance
- 112. (1) Sensorimotor coupling • Coupling between self and other at levels of body schema and body image.
- 113. (2) Putting yourself in someone else’s shoes • Builds on an immediate embodied sense of others as like oneself.
- 114. (2) Putting yourself in someone else’s shoes • Can be seen in consolation behavior in apes.
- 115. (3) Mutual self/other understanding • Sense of others as like oneself • Shared attention • Perspective taking
- 118. Alters brain function, disengages coping mechanisms, and compromises ability to execute rational choices Increases the likelihood of psychopathology: depression, drug abuse & violent behavior Genetic vulnerabilities affect particular behavioral outcomes of stress Positive attributes of individual or environment are protective Chronic stress primes the brain for maladaptive behavior and relapse
- 119. Ontogeny Short-term Phylogeny Long-term vs. Phenotype Evolution Genetics CNS complexity Epigenetics CNS plasticity ENVIRONMENTAL STRESSORS
- 120. «Αρχή επιστήμης η των ονομάτων επίσκεψις» Αντισθένης “The beginning of science is the visit of names” Antisthenes
- 121. Hebe, daughter of Zeus and Hera, the eternal adolescent, an Olympian Goddess
- 122. Hebe, the eternal adolescent, an Olympian goddess, often shown to look at her mirror image in the water
- 123. • Self-domestication • Juvenilization= Paedopomorphosis= Neoteny (human brain ontogeny complete at 25-27 y)