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Good Stress-Bad Stress Brain-Body Interactions and the Effects on Neural and Behavioral Function

Bruce S. McEwen, Ph.D. Alfred E. Mirsky Professor Head, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology The Rockefeller University, NY. Good Stress-Bad Stress Brain-Body Interactions and the Effects on Neural and Behavioral Function. STRESS. Many targets for cortisol.

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Good Stress-Bad Stress Brain-Body Interactions and the Effects on Neural and Behavioral Function

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  1. Bruce S. McEwen, Ph.D.Alfred E. Mirsky ProfessorHead, Harold and Margaret Milliken HatchLaboratory of NeuroendocrinologyThe Rockefeller University, NY Good Stress-Bad Stress Brain-Body Interactions and the Effects on Neural and Behavioral Function

  2. 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

  3. Restraint stress: delayed-type hypersensitivity Biphasic effect of stress on immune function: Dr. Firdaus Dhabhar

  4. Restraint stress: delayed-type hypersensitivity Biphasic effect of stress on immune function: Dr. Firdaus Dhabhar

  5. Mediators of allostasis leading to adaptation BIPHASIC AND NON-LINEAR 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

  6. Mediators of allostasis leading to adaptation BIPHASIC AND NON-LINEAR CNS Function -Cognition -Depression -Aging -Diabetes -Alzheimer’s Metabolism -Diabetes -Obesity Breaking down the silos of knowledge in biology and medicine!! Cortisol Inflammatory Cytokines DHEA Anti-inflammatory cytokines Sympathetic Parasympathetic Oxidative Stress Cardiovascular function -Endothelial cell damage -Atherosclerosis Immune function -immune enhancement -immune suppression

  7. Stress - a challenge to the body PROTECTION VS. DAMAGE External challenge Hypertension Normal basal Allostasis - leads to adaptation From hypertension or repeated challenge Low allostatic load Sterling and Eyer 1988; McEwen and Stellar 1993

  8. Emergency Life History Stage: Allostasis Ham Creek, Hudson Valley, NY John Wingfield, U Washington Behavioral and physiological responses to an emergency: 1. Find a refuge until conditions improve or the situation passes 2. Leave until conditions improve 3. Find a refuge at first and then leave if conditions do not improve 4. Mobilize stored energy 5. Settle in alternate habitat Role of glucocorticoids in respone to ELH 1. Suppress “unnecessary” physiological activity - eg. reproduction. 2. Mobilize energy reserves. 3. Activate alternative behavior patterns - eg locomotor activity

  9. Allostatic load Grizzly bear, Ursus horribilis, North Slope of Alaska Arctic ground squirrel, Spermophilus parryi, common prey item. Berries, Vaccinium sp., Common food item. Arctic willow, Salix sp., roots are a common food item. Putting on fat for the winter

  10. Consequences of allostatic overload Freeing up resources and providing food for progeny

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

  12. Social environment and health Health-related behaviors

  13. 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 overload Psychosocial stress is a major factor

  14. 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 Allostatic load score: extreme quartile of each measure; for above max score is 18 Dr. Teresa Seeman UCLA

  15. Some of the findings with allostatic load battery • Predictive of mortality over 7 years • 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.

  16. Social environment and health Central Role of the Brain

  17. The Human Brain Under Stress Three Key Brain Areas Under Investigation Prefrontal cortex Decision making, working memory, self regulatory behaviors: mood, impulses Helps shut off the stress response Hippocampus Memory of daily events; spatial memory; mood regulation Helps shut off stress response Amygdala Anxiety, fear; aggression Turns on stress hormones andincreases heart rate Amygdala Hippocampus

  18. Remodeling of neural architecture Dendrites Shrink and expand Synapses Disappear and are replaced Neurogenesis Continues in some brain areas

  19. Brain Under Stress Key role of excitiatory amino acids in plasticity and damage Hippocampus Contextual, episodic, spatial memory Mood regulation – target of depression Glutamate plays a key role Prevented by…. Blocking glucocorticoid synthesis Blocking NMDA receptors Lithium Dilantin Antidepressants Benzodiazepine Deficiency of BDNF Hippocampus Stress Atrophy

  20. # granule cells x 106 2.5 * control 3 wks stress 6 wks stress Brain Under Stress Effects of chronic stress on dentate gyrus neurogenesis Hippocampus Contextual, episodic, spatial memory Mood regulation – target of depression Stress decreases granule cell # Hippocampus Neurogenesis Stress inhibits neurogenesis

  21. CA3 dendritic remodeling in animal models Visible burrow – dominants as well as subordinates with Caroline and Robert Blanchard Tree shrew – intruder under chronic stress with Eberhard Fuchs Hibernation – rapid onset and rapid reversal with Paul Pevet

  22. Ongoing studies in mice by Drs. Jason Gray and Carla Nasca

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

  24. Acute Stress Increases H3K9me3 – increased repression? Dr. Richard Hunter

  25. Acute Stress Increases H3K9me3 and Represses DNA of Retrotransposon Loci that is trapped by Chromosome Immuno Precipitation………. …which reduces RNA that is transcribed from those loci

  26. Repressive histone marks in the hippocampus Progression from acute to chronic stress Dr. Richard Hunter What does this habituation mean for gene expression and genomic stabiity?

  27. Summary: Stress – Good and Bad Role in Synaptic Function, Adaptive Plasticity and Damage • Synaptic functions: suppression • Synaptic transmission. • Long-term potentiation. • Learning - less-important things • Adaptive plasticity ***: • Suppression of neurogenesis. • Mediates dendritic remodeling. • Synaptic functions: enhancement • Synaptic transmission. • Long-term potentiation. • Learning - re: self-preservation Loss of resilience > Neurochemical distortion > Impaired remodeling and lack of recovery from stress • Damage potentiation: • Mediates excitotoxicity • in seizures, stroke, & head trauma Increasing amounts and frequency Adrenal steroids and excitatory amino acids modulate both limbs of inverted U ***Chronic stress: how much protection vs. destabiization?

  28. The Human Hippocampus Under Stress Contextual, episodic, spatial memory Mood regulation – target of depression • HippocampusATROPHIESin: • 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 • Chronic inflammation Hippocampus Hippocampus

  29. The Human Hippocampus Under Stress The Positive Side of the Story • Hippocampus INCREASESin size with: • Regular exercise • Intense learning • Anti-depressant treatment Hippocampus

  30. Control Chronic stress Stress causes neurons to shrink or grow ….but not necessarily to die Control Chronic stress Amygdala OFC Prefrontal Cortex And Hippocampus

  31. Acute Immobilization Stress (AIS) putative model of Post Traumatic Stress Disorder (PTSD) amygdala Immobilization (2 hours) Delayed Effect Increased anxiety New spines in BlA Stress After 10 Days New spines induced without dendritic expansion 10d later Mitra et al PNAS ,2005 Roozendaal, McEwen and Chattarji Nat Rev Neuroscience 2009

  32. Acute Immobilization Stress (AIS) putative model of Post Traumatic Stress Disorder (PTSD) amygdala Immobilization (2 hours) Delayed Effect Increased anxiety New spines in BlA Stress After 10 Days New spines induced without dendritic expansion 10d later THIS IS PREVENTED BY ELEVATED GLUCOCORTICOIDS AT TIME OF ACUTE STRESSOR ! Mitra et al PNAS ,2005 Roozendaal, McEwen and Chattarji Nat Rev Neuroscience 2009

  33. Possible relevance to PTSD • Low CORT at time of trauma – increased PTSD • Epidemiology (Yehuda, McFarlane, Shalev) • Supplemental CORT reduces symptoms (Schelling) • Animal models (Hagit Cohen and colleagues)

  34. Brain Under Stress: Role in cognitive function, emotion, neuroendocrine and autonomic regulation Prefrontal cortex Decision making, working memory, Self regulatory behaviors: mood, impulses Autonomic and HPA regulation Reversible in young adults. _________ Sensitive to circadian disruption _________ Loss of resilience with aging --------------- Females respond differently Collaboration with John Morrison, Patrick Hof Mt Sinai School of Medicine Control mPFC Chronic stress Circadian disruption Amygdala Hippocampus

  35. Diverse Mechanisms of Adrenal Steroid Action

  36. published online 28 April 2013; doi:10.1038/nn.3387

  37. Keith Akama Karen Bulloch Matt Hill Jason Gray Richard Hunter Ilia Karatsoreos Yoav Letvin Conor Liston Ana Maria Magarinos Melinda Miller Carla Nasca Gus Pavlides Kara Pham Jason Radley Rebecca Shansky Joanna Spencer-Segal Sid Strickland Elizabeth Waters B.J. Casey, Weill/Cornell Sumantra Chattarji, Bangalore and MIT Patrick Hof,Mt Sinai Joseph Ledoux, NYU Teresa Milner, Weill/Cornell John Morrison, Mt Sinai Teresa Seeman, UCLA John Wingfield, UC Davis Recent and Current 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 Board of Children, Youth and Families (IOM) Support from NIA, NIMH and NINDS

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