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Protective and Damaging Effects of Mediators of Stress and Adaptation Central Role of the Brain

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.

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Protective and Damaging Effects of Mediators of Stress and Adaptation Central Role of the Brain

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  1. Protective and Damaging Effects of Mediators of Stress and AdaptationCentral 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

  2. “Stress” is part of life Two views of stress and anxiety!

  3. Social environment and health Central Role of the Brain Accumulation of load (“weathering”) with aging

  4. Mediators of allostasis leading to adaptation NETWORK OF ALLOSTASIS CNS Function -Cognition -Depression -Aging -Diabetes -Alzheimer’s Metabolism -Diabetes -Obesity Cortisol Inflammatory Cytokines DHEA Anti-inflammatory cytokines Sympathetic Parasympathetic Oxidative Stress Cardiovascular function -Endothelial cell damage -Atherosclerosis Immune function -immune enhancement -immune suppression

  5. 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

  6. 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

  7. Distribution of ALscored as being in extreme quartile of distribution of 1 or more of 17 parameters

  8. Allostatic Load & 7-yr MortalityMacAthur Successful Aging Study p-trend <0.0001

  9. 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.

  10. Social environment and health Stressors Trauma, abuse Major life events Environmental stressors (work, home, neighborhood)

  11. 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

  12. Social environment and health Central Role of the Brain Accumulation of load (“weathering”) with aging Biological embedding - early life experiences IN BOTH: EPIGENETIC REGULATION

  13. 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

  14. Social environment and health Health-related behaviors

  15. 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

  16. 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

  17. Social environment and health The Brain as a Target of Stress

  18. Remodeling of neural architecture In adult as well as developing brain Neurogenesis esp. in hippocampus Synapses Disappear and are replaced Dendrites Shrink and expand

  19. Control Stress causes neurons to shrink or grow ….but not necessarily to die Control Chronic stress Chronic stress Amygdala, orbitofrontal cortex Medial prefrontal cortex and hippocampus

  20. The Human Brain Under Stress Three of the Key Brain Areas Under Investigation Hippocampus Memory of daily events; spatial memory; mood regulation Helps shut off stress response Shrinkage of neurons; synapse loss Reduced neurogenesis Medial prefrontal cortex Decision making, working memory, self regulatory behaviors: mood, impulses Helps shut off the stress response Shrinkage of dendrites; loss of synapses Amygdala Anxiety, fear; aggression Turns on stress hormones andincreases heart rate Increased volume and activity Hypertrophy of neurons; increased synapses Prefrontal cortex Hippocampus Amygdala

  21. 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 Receptors in cell nuclei regulate gene expression “MR” and “GR” Hippocampus

  22. Stress, Glucocorticoids and other modulators Dentate gyrus - CA3: plasticity and vulnerability Vulnerable to damage. Dendrites shrink with stress but reversible!!! Neurogenesis reduced by stress Entorhinal Cortex input Mossy fiber terminals: glutamate release

  23. Summary: Stress – Good and Bad Role in Synaptic Function, Adaptive Plasticity and Damage • Synaptic functions: suppression • Synaptic transmission. • Long-term potentiation. • Learning - less-important • Synaptic functions: enhancement • Synaptic transmission. • Long-term potentiation. • Learning - re: self-preservation • Adaptive plasticity ***: • Suppression of neurogenesis. • Mediates dendritic remodeling. • Damage potentiation: • Mediates excitotoxicity • in seizures, stroke, & head trauma Increasing amounts and frequency ***Chronic stress: how much protection vs. destabiization? Mediated by glucocorticoids, excitatory amino acids, neurotrophins, cytokines

  24. The Hippocampus Under Stress • Hippocampus SHOWSATROPHY in: • Major depression • Type 2 diabetes • Post-traumatic stress disorder • Cushing’s disease Contextual, episodic, spatial memory Mood regulation – target of depression • ALSO as a result of: • Chronic stress • Chronic jet lag • Lack of exercise • Chronic inflammation Hippocampus

  25. Amygdala Under Stress Amygdala - Emotion, fear, anxiety, - Aggression - Turns on HPA and autonomic response Stress causes hypertrophy and increased activity, as in anxiety disorders and depression Amygdala

  26. 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

  27. Cortisol response– adaptation vs. damage STRESS Many targets for cortisol AVP CRH Cortisol ACTH Acute - enhances immune, Memory, energy replenishment, Cardiovascular function Chronic - suppresses immune, Memory, promotes bone Mineral loss, muscle wasting; Metabolic syndrome

  28. Diverse Mechanisms of Adrenal Steroid Action

  29. 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

  30. What about epigenetic regulation?Chromatin unfolding and folding:role of histones

  31. Acute Stress Increases H3K9me3 in hippocampus Increased repression Dr. Richard Hunter

  32. Acute stress – ChIP with antibodies to H3K9Me3Retrotransposon 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

  33. 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

  34. 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

  35. “Top down” effects on hippocampus • Hippocampus INCREASESin size with: • Regular exercise • Intense learning • Anti-depressant treatments – not only drugs • but also ECT and exercise Hippocampus

  36. Looking to the Future The adult brain shows plasticity and we are only beginning to recognize its potential! Neurogenesis Continues in some brain areas Synapses Disappear and are replaced Dendrites Shrink and expand

  37. 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 Collaborators Many colleagues to acknowledge! And to former students, postdoctoral fellows 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

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