Protective and Damaging Effects of Mediators Protective and Damaging Effects of Mediators of Stress and Adaptationof Stress and Adaptation

Central Role of the BrainCentral Role of the Brain

Bruce McEwen, Ph.D.Alfred E. Mirsky Professor and HeadHarold and Margaret Milliken HatchLaboratory of Neuroendocrinology

The Rockefeller University

Two views of stress and anxiety!

“Stress” is part of life

Social environment and healthCentral Role of the Brain

Accumulation of load (“weathering”) with aging

Cortisol

DHEA

Sympathetic

Parasympathetic

Inflammatory Cytokines

Anti-inflammatory cytokines

Oxidative Stress

Metabolism -Diabetes -Obesity

CNS Function -Cognition -Depression -Aging -Diabetes -Alzheimer’s

Cardiovascular function -Endothelial cell damage -Atherosclerosis

Immune function -immune enhancement -immune suppression

Mediators of allostasis leading to adaptation NETWORK OF ALLOSTASIS

Coronary Artery Risk Development in Young Coronary Artery Risk Development in Young Adults (CARDIA)Adults (CARDIA)

• Slides from Prof.Teresa Seeman, Ph.D. UCLA

• N ~ 5,000, ages 18-30 in 1985 —ages 33-45 at 15-yr follow-up in 2000

• 4 sites (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA)

• Stratified sampling - equal # by gender, ethnicity, age and education

• Followups = 1987, 1990, 1992, 1995, 2000

Allostatic Load Ancillary Study Allostatic Load Ancillary Study Year 2000 Exam (n=769) Year 2000 Exam (n=769)

• Cardiovascular— SBP & DBP— Heart Rate Variability

• Low Freq. Power• High Freq. Power• Heart rate

• Metabolism— HDL Cholesterol— LDL Cholesterol— Triglycerides— Fasting Insulin— Fasting Glucose

• Waist circumference

• Inflammation— Fibrinogen— CRP— IL-6

• SNS— Ur. Epinephrine— Ur. Norepinephrine

• HPA — Urinary Cortisol— Salivary Cortisol

• Am rise• Pm decline

Dr. Teresa Seeman UCLA

Distribution of ALDistribution of AL scored as being in extreme quartile of distribution of 1 or more of 17 parametersscored as being in extreme quartile of distribution of 1 or more of 17 parameters

Allostatic Load & 7-yr MortalityAllostatic Load & 7-yr Mortality MacAthur Successful Aging StudyMacAthur Successful Aging Study

p-trend <0.0001

Findings with allostatic load battery

Higher education - lower allostatic load score.

African Americans have higher AL scores and a flatter gradient across education.

Neighborhood poverty - higher AL scores

Social conflict - higher AL score.

Social support - lower AL score.

Social environment and healthStressors

Environmental stressors(work, home, neighborhood)

Major life events Trauma, abuse

Types of Stress

Positive Stress- Exhilaration from a challenge that has a satisfying outcome

- Sense of mastery and control

- Good self esteem

Tolerable Stress- Adverse life events but good social and emotional support

Toxic Stress- Exacerbated by chaos, abuse, neglect

- Poor social and emotional support-Unhealthy brain architecture-Genetic risk and early life adversity

Social environment and healthCentral Role of the Brain

Accumulation of load (“weathering”) with agingBiological embedding - early life experiences

IN BOTH: EPIGENETIC REGULATION

Anda et al / Am J Prev Med 2010;39(1):93–98

Adverse Childhood Experience (ACE) – Health Consequences

carried out in Kaiser-Permanente Health System in California

Heart disease, smoking, obesity

Drug abuse, high risk for AIDS

Depression, anxiety, anger control

Anti-social behavior

Social environment and healthHealth-related behaviors

What we often mean by “stress” is being “stressed out”!

Feeling overwhelmed, out of control, exhausted, anxious, frustrated, angry

What happens to us?

- Sleep deprivation

- Eating too much of wrong things, alcohol excess, smoking

- Neglecting regular, moderate exercise

All of these contribute to allostatic load Psychosocial stress is a major factor

Increased blood pressure; decreased parasympathetic tone.

Elevated evening cortisol, glucose, insulin.

Elevated inflammatory cytokines.

Increased appetite, which can increase 1-3 after over-eating.

Depressed mood.

Impaired cognitive function.

Sleep quality, social relationships and cytokines

POSITIVE SOCIAL RELATIONSHIPS ARE PROTECTIVE

Social environment and healthThe Brain as a Target of Stress

Remodeling of neural architectureIn adult as well as developing brain

Dendrites Shrink and expand

SynapsesDisappear and are replaced

Neurogenesis esp. in hippocampus

Control

Control

Chronic stress

Medial prefrontal cortex and hippocampus

Stress causes neurons to shrink or grow….but not necessarily to die

Chronic stress

Amygdala, orbitofrontal cortex

HippocampusMemory of daily events; spatial memory; mood regulation

Helps shut off stress response

Shrinkage of neurons; synapse loss

Reduced neurogenesis

AmygdalaAnxiety, fear; aggression

Turns on stress hormones and

increases heart rate

Increased volume and activity

Hypertrophy of neurons; increased synapses

Amygdala

Hippocampus

Medial prefrontal cortexDecision making, working memory,self regulatory behaviors: mood, impulses

Helps shut off the stress response

Shrinkage of dendrites; loss of synapses

The Human Brain Under StressThe Human Brain Under StressThree of the Key Brain Areas Under InvestigationThree of the Key Brain Areas Under Investigation

Prefrontal cortex

Memory of daily events, spatial memory

Mood regulation – target of depression

The Brain Under StressThe Brain Under StressReceptors for Adrenal Steroids in HippocampusReceptors for Adrenal Steroids in Hippocampus

Hippocampus

Adrenal steroid receptorsin hippocampus

Receptors in cell nuclei regulategene expression

“MR” and “GR”

Hippocampus

Vulnerable to damage.

Dendrites shrink with stressbut reversible!!!

Mossy fiber terminals: glutamate release

Stress, Glucocorticoids and other modulatorsDentate gyrus - CA3: plasticity and vulnerability

Neurogenesisreduced bystress

EntorhinalCortexinput

Summary:Summary: Stress – Good and Bad Stress – Good and Bad Role in Synaptic Function, Adaptive Plasticity and DamageRole in Synaptic Function, Adaptive Plasticity and Damage

Synaptic functions: enhancementSynaptic functions: enhancement Synaptic transmission. Long-term potentiation. Learning - re: self-preservation

Damage potentiation:Damage potentiation: Mediates excitotoxicityin seizures, stroke, & head trauma

***Chronic stress: how much protection vs. destabiization?

Adaptive plasticity ***:Adaptive plasticity ***: Suppression of neurogenesis. Mediates dendritic remodeling.

Increasing amounts and frequency

Synaptic functions: suppressionSynaptic functions: suppression Synaptic transmission. Long-term potentiation. Learning - less-important

Mediated by glucocorticoids, excitatory amino acids, neurotrophins, cytokines

The Hippocampus Under StressThe Hippocampus Under Stress

Hippocampus SHOWS ATROPHY in:

• Major depression

• Type 2 diabetes

• Post-traumatic stress disorder

• Cushing’s disease

Hippocampus

Contextual, episodic, spatial memory

Mood regulation – target of depression

ALSO as a result of:

•Chronic stress

•Chronic jet lag

•Lack of exercise

•Chronic inflammation

Amygdala

- Emotion, fear, anxiety,

- Aggression

- Turns on HPA and autonomic response

Stress causes hypertrophy

and increased activity, as in

anxiety disorders and

depression

Amygdala Under StressAmygdala Under Stress

Amygdala

Medial prefrontal cortexDecision making, working memory,Self regulatory behaviors: mood, impulsesAutonomic and HPA regulation

Medial Prefrontal Cortex Under StressMedial Prefrontal Cortex Under Stress

Impaired function from:

-Chronic perceived stress-Jet lag

Impaired development from:

-Physical and verbal abuse-Neglect-Chaos in home

Resulting in poor self regulatory behaviors, ie.:

-Reduced cognitive flexibility-Reduced emotional regulation-Increased impulsiveness-Increased propensity for drug abuse

CRHAVP

ACTH

Cortisol

STRESS

Acute - enhances immune,Memory, energy replenishment,Cardiovascular function

Chronic - suppresses immune,Memory, promotes boneMineral loss, muscle wasting;Metabolic syndrome

Many targets for cortisol

Cortisol response– adaptation vs. damage

Diverse Mechanisms of Adrenal Steroid Action

Epigenetics Biological Embedding

“above the genome”

Refers to the gene-environment interactions that bring about the phenotype of an individual.

- Modifications of histones - unfolding/folding of chromatin to expose or hide genes

- Binding of transcription regulators to DNA response elements on genes

- Methylation of cytosine bases in DNA without changing genetic code

- MicroRNA’s – regulate mRNA survival and translation

Effects can extend to next generationExamples: obesity; parental behaviorhttp://www.pbs.org/wgbh/nova/sciencenow/3411/02.html

What about epigenetic regulation?What about epigenetic regulation?Chromatin unfolding and folding:Chromatin unfolding and folding:

role of histonesrole of histones

Acute Stress Increases H3K9me3 in hippocampusAcute Stress Increases H3K9me3 in hippocampus Increased repression Increased repression

Dr. Richard Hunter

Acute stress – ChIP with antibodies to H3K9Me3Acute stress – ChIP with antibodies to H3K9Me3

Retrotransposon DNA that is repressed: i.e., enriched in immunoprecipitateRetrotransposon DNA that is repressed: i.e., enriched in immunoprecipitate

Dr. Richard Hunter

There is a corresponding decrease in expression of RNA’s coded by the DNA

What we are now finding out…..

Excitatory amino acids play a key role along with glucocorticoids….. …. and other mediators!

Chronic stress can shrink dentate gyrus and decrease neuron number

Acute stress activates repressive histone marks esp. in hippocampus.

This response selectively silences certain retrotransposon DNA elementsand decreases RNA production.

This response to an acute stressor habituates and may be lost after chronic stress and in aging and may contribute to genomic instability

What to do? Top-down therapies

Interventions - evidence that they change brain structure and function

Regular physical activityIncreased hippocampal volume and PFC blood flow

and improved executive function and memory

Cognitive-behavioral therapyReducing anxiety decreases amygdala volume

Social support and integrationExperience Corps for elderly volunteers

Improved executive function, PFC blood flow and overall health

Pharmaceutical agents as adjuncts to top down interventions and facilitators of change

““Top downTop down”” effects on hippocampus effects on hippocampus

Hippocampus

Hippocampus INCREASESin size with:

•Regular exercise

•Intense learning

•Anti-depressant treatments – not only drugs

but also ECT and exercise

Looking to the Future

Dendrites Shrink and expand

SynapsesDisappear and are replaced

NeurogenesisContinues in some brain

areas

The adult brain shows plasticity and we are only beginning to recognize its potential!

• Keith Akama• Karen Bulloch• Matt Hill• Richard Hunter• Ilia Karatsoreos• Conor Liston• Ana Maria Magarinos• Melinda Miller• Gus Pavlides• Donald Pfaff• Kara Pham• Jason Radley• Rebecca Shansky• Joanna Spencer-Segal• Sid Strickland• Elizabeth Waters• Zachary Weil

• B.J. Casey, Weill/Cornell• Sumantra Chattarji, Bangalore and MIT• Patrick Hof,MtSinai• Joseph Ledoux, NYU• Teresa Milner, Weill/Cornell• John Morrison, Mt Sinai

•

Current and Recent Colleagues and CollaboratorsCurrent and Recent Colleagues and Collaborators

MacArthur Research Network on Socioeconomic Status and Health

National Scientific Council on the Developing Child

Support from NIA, NIMH and NINDS

And to former students, postdoctoral fellows

and colleagues who have contributed so much

to this story!!!

Many colleagues to acknowledge!