Stress Growth and

Development of the Child

and the Adolescent

George P. Chrousos

National and Kapodistrian

University of Athens

G.P. Chrousos 2

Stress in Early Life

• Stress and Growth and

Development Concepts

• Stress Mechanisms

• Effects of the Stress System on

the Developing Organism

“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

Hebe, daughter of Zeus and Hera, the eternal adolescent, an Olympian Goddess

Ηβη, Hebe

Puberty vs. Adolescence

Ενήβωση vs. Εφηβεία

Ephebiatrics

Puberty vs. Adolescence

12-15 y 12- >>15 y

Ενήβωση vs. Εφηβεία

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

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)

The Human Brain

• Plato (Meno)

The innate preformation theory

(Genetic view)

• Aristotle

The blank state theory

(Epigenetic view)

A. THE DEVELOPING BRAIN

Birth 2y Puberty Adulthood

No. of

synap

ses/

2-D

eoxy

glu

cose

upta

ke

Pruning / Neuronal Darwinism

Cognitive and Language Development

Synaptogenesis

Pruning

Ερεθίσματα και Εγκέφαλος

"Use it or lose it"

The brain loses the nervous circuits that are not used !

G.P. Chrousos 22

Functional Networks

Fair et al. PLOs 2009

The Stream of Consciousness

Default Mode Network

50% of resting brain energy

ADULT: PFC, cingulate c, parietal c

NEWBORN: Visual cortex

Default Network

Fair et al. PNAS 2008

Brain plasticity research

suggests that experience can

change neural patterns, for

better or for worse.

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

Humans as Complex

Biological Systems

• Organism

• Society

“Resonance”, “mirror” and “spindle”

(von Economo) neurons

“Emotional Epidemiology”

Phenomenology of empathy

Edith Stein (1891-1942). On the Problem of

Empathy (1916).

Edmund Husserl (1859-1938).

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”

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”

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 Lama.

Stress in Early Life

Growth: Stature, Body weight, Body composition,

Body shape, Puberty

Development: Adjustment, Psychopathology

Concurrent and/or Adult Pathology

Vulnerability of Developing Organisms

• Development/Tissue formation

• Increased metabolic rate

• Decreased DNA repair

• Decreased liver metabolism/xenobiotics

• Decreased immune function

• Decreased BBB

• Programming

Pythagoras 6th century BCE

Disturbing

Forces

Harmony

Equilibrium

Balance

Counteracting

Reestablishing

Forces

IIIIII

Stressors HomeostasisAdaptive

Response(Physical,

Emotional)

Pythagoras= Harmony

Alcmaeon=Iso-nomia

Walter Cannon= Homeostasis

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

Homeostasis over Time

Healthy Baseline Homeostasis Baseline Homeostasis=Eustasis

Deteriorated Homeostasis=Cacostasis

Improved Homeostasis=Hyperstasis

Distress

Homeostasis over Time

Healthy Baseline Homeostasis = Eustasis

Deteriorated Homeostasis = Cacostasis

Improved Homeostasis = Hyperstasis

Human StressorsDaily 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 sleep

“Jet-lag”, biological clock uncoupling

Meta-modern “cyborg” stress

Stressors in Developing

Humans

Intrauterine stress

Early life stress: Lack or loss of caregiver support

(Attachment, Bonding, Neglect, Abuse), trauma,

puberty

HOMEOSTATIC SYSTEMS

• Amygdala (Fear/Anger)

• MCLS (Reward)

• Stress - CRH/LC-NE

• Cardiorespiratory

• Metabolic

• Immune

• Fatigue - Pain

• Sleep

• Biologic clock

Deficiency Optimum Excess

Ho

meo

sta

tic E

ffect

Homeostatic System Activity

Eustasis

Allostasis

Caco-

Allostasis

Caco-

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 SYSTEMSCHRONIC FUNCTIONING/DYSFUNCTIONING

“CRITICAL” PERIODS OF LIFE

Prenatal, Early Childhood, Puberty

Organizational Effects of Hormones(Stress, sex and immune hormones)

Stress in Early Life

• Stress and Growth and

Development Concepts

• Stress Mechanisms

• Effects of the Stress System on

the Developing Organism

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

Behavior

Development,

Aging

Reproductive

System

Immune

System

Growth

HPA Axis

LC/NE System

HPA Axis

Wakefulness/Slee

p

Biologic Clock

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

GH/IGF-1

LH/T

TSH/T3

F NE/E

iCRHIL-6

STRESS SYSTEM

Amygdala CRH

HIPPOCAMPUS

CRH/AVP LC/NE

ACTH

Inflammation

+

Sickness syndrome

Acute Stress

MCLS AMYGDALA

CRH

PVN

CRH/AVP

LC/NE

+

+

+

+

-

-

HIPPO-

CAMPUS

Cortisol Catecholamines/IL-6

Behavioral

adaptation

Physical

adaptation

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

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

InflammatoryNutritional

Oxidative

Cellular Stress

Cellular Stress

Inflammatory

NF-kBNFAT5

Nutritional

IR

Oxidative

MitochondriaKeap1 (SH sensor)-Nrf2-ΑRΕ

Stress in Early Life

• Stress and Growth and

Development Concepts

• Stress Mechanisms

• Effects of the Stress System on

the Developing Organism

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

Stress and Development

Later Effects of Stress :

•Obesity

•Metabolic Syndrome

•Early Adrenarche, Puberty

•Polycystic Ovary Syndrome

•Osteoporosis

•Behavioral/Psychosomatic Disorders

STRESS SYSTEM ACTIVITY

Low Range “Normal” Range High Range

Handling Natural Maternal Separation

Per

cent

subje

cts

CRH Progressively Increases with

Repeated Separation Stress of Infant

Macaques

PR: Peer-RearedMR: Mother-Reared

Systolic and Diastolic

Blood Pressure-SDS

*

p=

Systolic Blood Pressure

Comparison between SGA-IVF, AGA-IVF

and controls

Triglycerides

Comparison between IVF and controls

PREGNANCY

FETUS

Increased Nutrition,

Gestational diabetesDecreased Nutrition, Stress

Insulin

IGF-1

Cortisol

Catecholamines

LGASGA

Visceral Adiposity

Metabolic Syndrome

Acute Stress

MCLS AMYGDALA

CRH

PVN

CRH/AVP

LC/NE

+

+

+

+

-

-

HIPPO-

CAMPUS

Cortisol Catecholamines/IL-6

Stress Hyper-responsive

Child/Adult

MCLSAMYGDALA

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

GENETIC VARIATION

DEVELOPMENTAL HISTORY STRESSReal or perceived

HPA axis

Endothelial Dysfunction/Inflammation

Atherosclerosis

Cardiovascular Disease

Insulin resistance

Visceral Obesity=Metabolic

Syndrome

Sarcopenia

DM type 2TG

LDL

HDL

ABP

APR

Cytokines

Stress systemCRH/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 ApneaSickness Syndrome

PCOS

0

2

4

6

8

10

12

20 30 40 50 60

IL-6

(pg/m

l)

r = .790

p = .000

0

1

2

3

4

5

20 30 40 50 60

TN

Fa

(pg/m

l)r = .400

p = .014

BMI

Both IL-6 and TNFa correlate with BMI

JCEM 1997

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

24 H SAMPLING OVERNIGHT

DEXAMETHASONE TESTA.

B.

PL

AS

MA

CO

RT

ISO

L

8 am 8 pm 8 am

TARGET TISSUE SENSITIVITY

TA

RG

ET

TIS

SU

E R

ES

PO

NS

E

CORTISOL CONCENTRATION

HS N R THRESHOLDFOR HARMFULNESS

-D

-D

+D

+D

NS CS

NS CS

24 H

CO

RT

ISO

L

DARK

Chrousos, IJO 1998

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

Uncoupling between Circadian Rhythm of Circulating Cortisol and Tissue Glucocorticoid Sensitivity Produces Pathology

8 am 8 pm 8 amDark

Ta

rge

t T

iss

ue

Glu

co

co

rtic

oid

Ac

tio

n

CIRCADIAN TISSUE GLUCOCORTICOID ACTION

OVERNIGHT

DEXAMETHASONE TESTP

las

ma

Co

rtis

ol

-D

-D

+D

+D

NS SS8 am 8 pm 8 amDark

24 H SAMPLING

Normal Stress Shift

Post Long Periods of Stress

Neoplasia Rx

Anorexia Nervosa

Malnutrition

Extreme Athleticism

Dependencies

THE STRESS SYSTEM AND THE METABOLIC SYNDROME

2 1 3

Str

ess

Sy

stem

Act

ivit

y

Stressor Potency

Basal

Max

Sen

se o

f W

ell-

Bei

ng/P

erfo

rmance

Stress System Activity

Optimum

3 21

DEPRESSION

visceral fat

cortisol

catecholamines

Melancholic Atypical

Metabolic Syndrome

visceral fat

lean body mass

bone mass

cortisol

catecholamines

insulin

80

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

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

DNA variation

Histone modification

Phenotype

DNA methylation

Protein

CH3

HDACMeCP2

NCoR

Recruitment of HDACs & corepressors

Binding of methyl-CpG binding proteins

GENETIC MACHINERYENVIRONMENTAL TRIGGERS

Smoking

Exercise

Toxins

Diet

Infection

Stress

Cold

Heat

Drugs

Fetal Life

Childhood

Puberty/

Adolescence

Fertility

Adulthood

Conceptio

n

The first generation that will die younger than their

parents

Finding Molecules

that Potentially Alter GR Action

Yeast Two-hybrid Screening

Using GR Fragments as Baits

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

CLOCK/BMAL1 Represses GR-induced Transcriptional Activity through Acetylation

GREs

GR

GR-induced

Transcriptional Activity

In the Absence of Acetylation by CLOCK

BMAL1

CLOCKAcetylation

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

Major, Recurrent Environmental Changes on

the Earth

Day/Night Changes

(Recurrent Stress)

Seasonal Changes

Rotation of the Earth:

Revolution of the Earth:

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

Circadian Fluctuation of Plasma Cortisol

24 hr Plasma Cortisol Sampling

Pla

sm

a C

ort

iso

l

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)

• 10-15 % of the mammalian

transcriptome oscillates with a 24 h

rhythm.

• CLOCK System-controlled genes and

downstream output genes are involved.

Nader, Chrousos, Kino, TEM 2010

Kino T

NICHD/NIH

CLOCK-mediated Gene-specific Regulation of

Glucocorticoid Action at Peripheral Tissues

Pla

sm

a C

ort

isol

8 am 8 pm Dark

8 am 8 pm Dark

Ta

rge

t T

issue

Glu

co

co

rtic

oid

Actio

n

CIRCADIAN TISSUE GLUCOCORTICOID ACTION

24 hr SAMPLING

8 am

8 am

Gene- (and Tissue-) specific

Changes of Glucocorticoid-

Responsive Genes

(Transactivation/transrepressi

on)

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

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

The developmental trajectories through

adolescence and into adulthood

Birth Childhood Puberty Early adulthood

Developmental Stage

Develo

pm

en

tal co

urs

e

Hormonal

activational and

organizational

effects on brain

and behavior

Continuity in adjustment

Transient adolescent

maladjustment

Adolescent maladjustment

leading to adult psychiatric

disorder

Inte

rnal

izat

ion s

ym

pto

ms

Chronological age

Hayward et al., JAACAP, 1997 Nottelmann et al., J. Peds, 1987

Inte

rnal

izat

ion s

ym

pto

ms

Chronological age

Early maturers

Late maturers Early maturers

Late maturers

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

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.

• Emotional “comfort” eating, lack of

sleep, impulsive behaviors and

selection of specific foods often

characterize stressed individuals. .

• Obese children and adolescents are

frequently entangled in a vicious cycle

between distress impairing self-image

and distorted self-image maintaining

and worsening distress.

Pain/Neural

Afferent

Program

Stress

Syndrome

Sickness

Behavior

Acute Phase

Reaction

Inflammatory (Sickness)

Syndrome

Stress

Syndrome

Anxiety/Depression

Metabolic s. / DM T2/

Sleep Apnea/PCOS

CVD, Cancer

Other

Obesity

Stress

Inflammation

“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

Prevalence of BMI≥85th and ≥ 95th Percentile

of 15 y of Age: Consensus Statement, 2004

Speiser, 2005

BMI curves, 2001

Boys Girls

BMI Curves in Relation to BMI 25 or 30

Boys Girls

A self-specifying

(autonomous) system in

dynamic coupling with its

milieu.

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:

(1) Sensorimotor coupling

• Imitation, sensorimotor

matching.

(1) Sensorimotor coupling

• Emotion sharing,

affective resonance

(1) Sensorimotor coupling

• Coupling between self

and other at levels of

body schema and

body image.

(2) Putting yourself in someone else’s

shoes

• Builds on an

immediate embodied

sense of others as like oneself.

(2) Putting yourself in someone else’s

shoes

• Can be seen in

consolation behavior

in apes.

(3) Mutual self/other understanding

• Sense of others as

like oneself →

• Shared attention →

• Perspective taking

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

OntogenyShort-term

PhylogenyLong-term

vs.

Phenotype

Evolution

Genetics

CNS complexity

Epigenetics

CNS plasticity

ENVIRONMENTAL STRESSORS

«Αρχή επιστήμης η των ονομάτων

επίσκεψις»

Αντισθένης

“The beginning of science is the visit of

names”

Antisthenes

Hebe, the eternal adolescent,an Olympian goddess,

often shown to look at her mirror image in the water

• Self-domestication

• Juvenilization=

Paedopomorphosis=

Neoteny (human brain ontogeny

complete at 25-27 y)

Choanoflagellatess