Download Stress

Protective and Damaging Effects of Mediators
of Stress and Adaptation
Central Role of the Brain
Bruce McEwen, Ph.D.
Alfred E. Mirsky Professor and Head
Harold and Margaret Milliken Hatch
Laboratory of Neuroendocrinology
The Rockefeller University
“Stress” is part of life
Two views of stress and anxiety!
Social environment and health
Central Role of the Brain
Accumulation of load (“weathering”) with aging
CNS Function
-Cognition
-Depression
-Aging
-Diabetes
-Alzheimer’s
Mediators of allostasis leading to adaptation
NETWORK OF ALLOSTASIS
Metabolism
-Diabetes
-Obesity
Cortisol
Inflammatory Cytokines
DHEA
Sympathetic
Parasympathetic
Cardiovascular function
-Endothelial cell damage
-Atherosclerosis
Anti-inflammatory cytokines
Oxidative Stress
Immune function
-immune enhancement
-immune suppression
Coronary Artery Risk Development in Young
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
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 AL
scored as being in extreme quartile of distribution of 1 or more of 17 parameters
140
120
# of participants
100
80
60
40
20
Std. Dev = 3.17
Mean = 5
N = 769.00
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
Allostatic Load & 7-yr Mortality
MacAthur Successful Aging Study
5
4.5
p-trend <0.0001
4
3.5
Rel. Risk
3
2.5
2
1.5
1
Allo 2
Allo 3
Allo 4
Allo 5
Allo 6
Allo 7+
Allostatic Load Scores (reference group = score of 0)
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 health
Stressors
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 health
Central Role of the Brain
Accumulation of load (“weathering”) with aging
Biological embedding - early life experiences
IN BOTH: EPIGENETIC REGULATION
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
Anda et al / Am J Prev Med 2010;39(1):93–98
Social environment and health
Health-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
Sleep quality, social relationships and cytokines
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.
POSITIVE SOCIAL RELATIONSHIPS ARE PROTECTIVE
Social environment and health
The Brain as a Target of Stress
Remodeling of neural architecture
In adult as well as developing brain
Dendrites
Shrink and expand
Synapses
Disappear and are replaced
Neurogenesis
esp. in hippocampus
Stress causes neurons to shrink or grow
….but not necessarily to die
Control
Control
Chronic stress
Chronic
stress
Medial prefrontal cortex
and hippocampus
Amygdala,
orbitofrontal cortex
The Human Brain Under Stress
Three of the Key Brain Areas Under Investigation
Medial prefrontal cortex
Decision making, working memory,
self regulatory behaviors: mood, impulses
Helps shut off the stress response
Shrinkage of dendrites; loss of synapses
Hippocampus
Memory of daily events; spatial
memory; mood regulation
Helps shut off stress response
Shrinkage of neurons; synapse loss
Reduced neurogenesis
Prefrontal cortex
Amygdala
Anxiety, fear; aggression
Turns on stress hormones
Amygdala
Hippocampus
and
increases heart rate
Increased volume and activity
Hypertrophy of neurons;
increased synapses
The Brain Under Stress
Receptors for Adrenal Steroids in Hippocampus
Memory of daily events, spatial memory
Mood regulation – target of depression
Adrenal steroid receptors
in hippocampus
Hippocampus
Hippocampus
Receptors in cell nuclei regulate
gene expression
“MR” and “GR”
Stress, Glucocorticoids and other modulators
Dentate gyrus - CA3: plasticity and vulnerability
Vulnerable to damage.
Dendrites shrink with stress
but reversible!!!
Neurogenesis
reduced by
stress
Mossy fiber terminals:
glutamate release
Entorhinal
Cortex
input
Summary: Stress – Good and Bad
Role in Synaptic Function, Adaptive Plasticity and Damage
Synaptic functions: suppression
Synaptic functions: enhancement
 Synaptic transmission.
 Long-term potentiation.
 Learning - re: self-preservation
 Synaptic transmission.
 Long-term potentiation.
 Learning - less-important
Adaptive plasticity ***:
 Suppression of neurogenesis.
 Mediates dendritic remodeling.
Damage potentiation:
 Mediates excitotoxicity
in seizures, stroke, & head trauma
Increasing amounts and frequency
Mediated by glucocorticoids, excitatory amino acids, neurotrophins, cytokines
***Chronic stress: how much protection vs. destabiization?
The Hippocampus Under Stress
Contextual, episodic, spatial memory
Hippocampus SHOWS ATROPHY in:
Mood regulation – target of depression
• Major depression
• Type 2 diabetes
• Post-traumatic
stress disorder
• Cushing’s disease
ALSO as a result of:
•Chronic stress
•Chronic jet lag
•Lack of exercise
Hippocampus
•Chronic inflammation
Amygdala Under Stress
Amygdala
- Emotion, fear, anxiety,
- Aggression
- Turns on HPA and
autonomic response
Stress causes hypertrophy
Amygdala
and increased activity, as in
anxiety disorders and
depression
Medial Prefrontal Cortex Under Stress
Medial prefrontal cortex
Decision making, working memory,
Self regulatory behaviors: mood,
impulses
Autonomic and HPA regulation
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
Cortisol response– adaptation vs. damage
STRESS
AVP
CRH
Many targets
for cortisol
Cortisol
ACTH
Acute - enhances immune,
Memory, energy replenishment,
Cardiovascular function
Chronic - suppresses immune,
Memory, promotes bone
Mineral loss, muscle wasting;
Metabolic syndrome
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 generation
Examples: obesity; parental behavior
http://www.pbs.org/wgbh/nova/sciencenow/3411/02.html
What about epigenetic regulation?
Chromatin unfolding and folding:
role of histones
Acute Stress Increases H3K9me3 in hippocampus
Increased repression
Dr. Richard Hunter
Acute stress – ChIP with antibodies to H3K9Me3
Retrotransposon DNA that is repressed: i.e., enriched in immunoprecipitate
Number of Islands
80000
60000
40000
20000
0
p
sU
s
e
Str
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ow
D
s
es
Str
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 elements
and 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 activity
Increased hippocampal volume and PFC blood flow
and improved executive function and memory
Cognitive-behavioral therapy
Reducing anxiety decreases amygdala volume
Social support and integration
Experience 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 down” effects on hippocampus
Hippocampus INCREASES
in size with:
•Regular exercise
•Intense learning
•Anti-depressant
treatments – not only drugs
but also ECT and exercise
Hippocampus
Looking to the Future
The adult brain shows plasticity and we are only beginning to recognize its potential!
Dendrites
Shrink and
expand
Synapses
Disappear and are replaced
Neurogenesis
Continues in some brain areas
Many colleagues to acknowledge!
Current and Recent Colleagues and Collaborators
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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
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B.J. Casey, Weill/Cornell
Sumantra Chattarji, Bangalore and MIT
Patrick Hof,MtSinai
Joseph Ledoux, NYU
Teresa Milner, Weill/Cornell
John Morrison, Mt Sinai
And to former students, postdoctoral fellows
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and colleagues who have contributed so much
to this story!!!
MacArthur Research Network on Socioeconomic Status and Health
National Scientific Council on the Developing Child
Support from NIA, NIMH and NINDS