protective and damaging effects of mediators of stress and adaptation central role of the brain
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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. - PowerPoint PPT PresentationTRANSCRIPT
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!