Types of Stress. We All Experience Stress. I declare that I have no potential conflicts of interest

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1 Resilience is the ability to achieve a successful outcome in the face of adversity National Scientific Council on the Developing Child Bruce S. McEwen, Ph.D. Alfred E. Mirsky Professor and Head, Harold and Margaret Milliken Hatch I declare that I have no potential conflicts of interest Laboratory of Neuroendocrinology, The Rockefeller University, NY, NY, USA YOUR INSTITUTION S LOGO We All Experience Stress : Target for Stress! Gateway to discovering hormone actions on the cognitive and emotional brain (1968) Receptors for glucocorticoids But we don t fully understand what it is... and how our bodies defend us. How does all of this get under our skin? What does it do to our brain and body? And what can we do about it? Adrenal steroid receptors in hippocampus Receptors in cell nuclei regulate gene expression Steroid autoradiography MR and GR Cortisol has biphasic effects on memory and neuron excitability Important role in mood regulation Wear and tear over the lifetime: aging, dementia The Brain as a Primary Organ of Stress Perception and Response Environmental ors (work, home, neighborhood) Individual differences Major life events Trauma, abuse Perceived (threat / no threat; helplessness; vigilance) Types of Stress Positive Stress Exhilaration from a challenge that has a satisfying outcome Behavioral (fight or flight; personal behavior diet, smoking, drinking, exercise) (genes, development, experience) Physiologic ALLOSTASIS ADAPTATION ALLOSTATIC LOAD Allostasis and allostatic load: What keeps us alive can also kill us! McEwen, New England Journal of Medicine

2 Types of Stress Types of Stress Positive Stress Positive Stress Exhilaration from a challenge that has a satisfying outcome Exhilaration from a challenge that has a satisfying outcome Tolerable Stress Tolerable Stress Adverse life events but good social and emotional support Adverse life events but good social and emotional support Toxic Stress lack of sense of control Poor social and emotional support Compromised brain architecture due to early life adversity Context-sensitive genotype makes it worse Adaptation to Experiences The Same Mediators that Allow Us to Adapt Also Cause Damage When Overused and Out of Balance allostasis Allostasis, the active process that promotes adaptation, emphasizes anticipation, prediction 5 kg 5 kg 500 kg 500 kg Sterling, P., Eyer, J., Allostasis: A New Paradigm to Explain Arousal Pathology, in: Fisher, S., Reason, J. (Eds.), Handbook of Life Stress, Cognition and Health. John Wiley & Sons, New York, pp Allostatic Load Sterling, P., Homeostasis vs allostasis: implications for brain function and mental. JAMA Psychiatry 71, The Brain as a Primary Organ of Stress Perception and Response Environmental ors (work, home, neighborhood) Individual differences Major life events Trauma, abuse Perceived Conditions/Experiences that Get Under the Skin and Dysregulate Physiology HEALTH DAMAGING BEHAVIORS from being ed out! Diet: quality and quantity of food (threat / no threat; helplessness; vigilance) Behavioral (fight or flight; personal behavior diet, smoking, drinking, exercise) (genes, development, experience) Physiologic Allostasis Lack of physical activity Alcohol Smoking Loneliness Circadian disruption: jet lag, shift work, sleep deprivation Adaptation Allostatic load Allostasis and allostatic load: What keeps us alive can also kill us! Ugly, noisy, polluted neighborhood; lack of green space ALL HAVE EFFECTS, WHETHER OR NOT CALLED STRESS McEwen, New England Journal of Medicine

3 We Need Cortisol to Stay Alive! STRESS We Need Cortisol to Stay Alive! Many targets for cortisol AVP Many targets for cortisol CRH AVP CRH Cortisol ACTH Cortisol ACTH Acute - enhances immunity, memory, energy replenishment, cardiovascular function Acute - enhances immunity, memory, energy replenishment, cardiovascular function Chronic - suppresses immunity, memory; promotes bone mineral loss, muscle wasting, metabolic syndrome Chronic - suppresses immunity, memory; promotes bone mineral loss, muscle wasting, metabolic syndrome More than Cortisol Mitochondrial allostatic load Mediators of Allostasis and System-wide Effects CNS: cognitive and mental Cardiovascular STRESS Martin Picard, Robert-Paul Juster and Bruce S. McEwen Metabolic Immunological Stress-related metabolic changes contribute to multiple. The disease cascade and mitochondrial allostatic load. Allostatic load is a pathophysiological process in which multisystem biological dysregulation caused by chronic synergizes with unhealthy behaviours. «SILO MEDICINE» Multi-morbidity Musculoskeletal pain From left to right none, one, two, 3 or more other Asthma Gastro problem CVD COPD Obesity Diabetes Hypertension Depression Osteoporosis Expertgroups & task forces Expertgroups & task forces PaCentorganizaCons PaCent- Fragmenting PaCentapproach PaCentPaCentGastro organizacons organizacons organizacons organizacons Guideline overflow Industrysponsors Expertgroups & task forces Industry-«One Industrysize fits sponsors sponsors Industryall?» sponsors Uncoordinated polypharmacy Expertgroups Expertgroups & task forces & task forces Expertgroups & task forces PaCentorganizaCons Industrysponsors Industrysponsors 3

4 The Brain as a Primary Organ of Stress Perception and Response Major life events Environmental ors (work, home, neighborhood) Remodeling of Neural Architecture Trauma, abuse Perceived (threat / no threat; helplessness; vigilance) Individual differences Behavioral (fight or flight; personal behavior diet, smoking, drinking, exercise) (genes, development, experience) Physiologic ALLOSTASIS ADAPTATION ALLOSTATIC LOAD Allostasis and allostatic load: What keeps us alive can also kill us! Dendrites Synapses Shrink and expand Disappear and are replaced Neurogenesis Continues in some brain areas McEwen, New England Journal of Medicine 1998 Regular Oscillations in Cortisol Levels Promote Dendritic Spine Turnover (Dr. Conor Liston, Weill Cornell) Circadian Rhythm of Cortisol Morning wakening (gets us going for the day) A FLAT RHYTHM IS BAD NEWS! cortisol levels Wisdom of the Body If oscillations stop, learning and performance suffers. Elevation at night causes obesity and can promote diabetes Accelerating Activity Decelerating Activity Wind Down Physical Repair Psychological Repair The Stressed Glutamatergic Synapse and Link to Cortisol Stress induces strong elevation of extracellular glutamate levels that is dependent on adrenal glands Contextual, episodic, spatial memory Mood regulation target of depression Control Chronic Chronic effects on dendritic remodeling are blocked by blocking NMDA receptors, as well as blocking adrenal steroid synthesis Neurogenesis Stress inhibits neurogenesis Neurogenesis recovers after chronic and is accelerated by physical activity Magarinos AM, McEwen BS, 95 4

5 Contextual, episodic, spatial memory Mood regulation target of depression Causes of hippocampus ATROPHY : Major depression Type 2 diabetes Post-traumatic disorder Cushing s disease size INCREASES with: Regular exercise Intense learning Anti-depressant treatment ALSO as a result of: Chronic Chronic jet lag Lack of exercise Chronic inflammation You are never too young or too old to benefit!! Regular physical activity is the most important behavior that we can do to maintain brain and body health. Left Right Baseline 6-months 1-year Baseline 6-months 1-year Stress Causes Neurons to Shrink or Grow Stress, Glucocorticoids and the Basolateral Control Chronic Control Chronic Chronic - expansion of dendrites; increased spine density; increased anxiety Acute traumatic or - delayed increase in spine density - delayed increase in anxiety - can be prevented by CORT elevation during or right after trauma In humans CORT elevation during or after trauma reduces PTSD symptoms Prefrontal Cortex & Impaired memory, mood, self-regulation Increased anxiety and vigilance Shona Chattarji 5

6 Prefrontal cortex - and aging Medial PFC neurons - dendrite shrink with chronic Sex Hormone Action and Sex Differences in the Brain The entire brain has receptors for sex hormones in both male and female Orbitofronal cortex neurons dendrite expand with chronic Many of these receptors mediate non-genomic effects on cytoskeleton, neurotransmitter release, mitochondrial function. Recovery of dendrites impaired with aging Sex differences involve not only hormonal programming but also X and Y chromosomes and mitochondrial DNA inherited from the mother Jason Radley, Conor Liston, Erik Bloss In a study on medical students, high perceived - associated with reduced cognitive flexibility - reduced functional connectivity involving PFC. These alterations recover - after a vacation. John Morrison Synapse turnover in estrous cycle Conor Liston, B.J. Casey Non-genomic estrogen receptors in synapses Men and women do equally well on this test. Social Environment and Health Environmental ors (work, home, neighborhood) Individual differences Major life events Trauma, abuse Perceived (threat / no threat; helplessness; vigilance) (genes, development, experience) Chaos in Home Greater helplessness and di, poor self-regulatory behavior Behavioral (fight or flight; personal behavior diet, smoking, drinking, exercise) Brain development: prefrontal cortex development is altered Obesity, elevated blood pressure, and cardiovascular reactivity Adverse Childhood Experience Abuse, Neglect, Poverty Physiologic Allostasis Developmental Issues for Children Adaptation Allostatic load Increases depression, substance abuse, antisocial behavior, cardiovascular disease, obesity Brain structure is altered for greater vigilance and anxiety Role of Early Life Stress 6

7 Contextual, episodic, spatial memory Is smaller in - Poverty - Low self esteem - Risk for PTSD Emotion, fear, anxiety, Aggression Larger and more active in depression, anxiety Larger in children living with a depressed mother Prefrontal cortex Decision making, working memory, Self regulatory behaviors: mood, impulses Underdeveloped with chaos of poverty, early life abuse WE CANNOT ROLL BACK THE CLOCK! Changing the direction of the life course From Halfon et al 2014 Positive vs Negative Direction INTERVENTIONS TO PROMOTE RESILIENCE that OPEN WINDOWS OF PLASTICITY and change brain structure and function Regular physical activity Increased hippocampal volume and PFC blood flow and improved executive function and memory Erickson, Kramer and colleagues Proc Natl Acad Sci U S A : Looking to the Future The adult brain shows plasticity and we are only beginning to recognize its potential! Mindfulness-Based Stress Reduction Reducing anxiety decreases amygdala volume Holzel Lazar. Soc Cogn Affect Neurosci : Social support and integration Experience Corps for elderly volunteers Improved executive function, PFC blood flow and overall health Carlson, Erickson, Kramer, Seeman, Fried, J Gerontol A Biol Sci Med Sci : Meaning and purpose (eudaimonia) Dendrites Shrink and expand Synapses Disappear and are replaced Neurogenesis Continues in some brain areas 7

8 Stress Colleagues and Collaborators Leiden University Nicole Datson Ron de Kloet Medical College of Wisconsin Cecilia Hillard Paolo de Angelis Josh Kogan Hilary Lambert Gordon Petty Todd Rubin Dani Zelli Adelaide Acquaviva Maryse Aubourg Halina Korsun The group Benedetta Bigio Nicole Bowles Lisa Eiland Jason Gray Matt Hill Richard Hunter Ilia Karatsoreos Yoav Litvin Jordan Marrocco Melinda Miller Carla Nasca Constantine Pavlides Weill/Cornell Kevin Bath B.J. Casey Francis Lee Conor Liston Teri Milner NYU Joe Ledoux Stanford University Natalie Rasgon Columbia University Martin Picard Robert Paul Juster Mt. Sinai Schl Med Erik Bloss Deena Goldwater Patrick Hof John Morrison Jason Radley Rebecca Shansky National Centre for Biological Sciences (Bangalore) Sumantra Chattarji Neuroimmune Ana Pereira Rajnish Rao and inflammation Program MacArthur Research Network for Socioeconomic Status and Health; Dr. Karen Bulloch National Scientific Council for the Developing Child 8