Transcript 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 n 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 • • • • • • • • • • • • • • • • • 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 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