The physiological response of stress

Transcription

1 Master Biologie-Santé TC4 Stress and vulnerability to depression - An allostatic perspective Cyril Rivat Université de Montpellier cyril.rivat@umontpellier.fr The physiological response of stress Stress describes experiences that are challenging emotionally and physiologically «Good stress» «Bad stress» Experiences that are of limited duration Sense of accomplishment Experiences that are of prolonged or recurrent Sense of control is lacking Physiologically adapted Emotionnaly/physically 1

2 The physiological response of stress Hans Selye ( ) was the first to define the stress and the stress response The physiological response of stress General adaptation syndrome from Hans Selye 2

3 The physiological response of stress + NA, A Adaptive response (Fight or flight) The physiological response of stress Effects of cortisol on the organism 3

4 The physiological response of stress Effects of cortisol on brain structures The physiological response of stress Memory Anxiety Decision making Effects of cortisol on cognitive functions brain 4

5 The pathophysiological response of stress HPA hyperactivity Desadaptive response Why depression? Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders. In 2014, 7% of Americans over the age of 12 reported depression within the past two weeks (Center for Disease Control and Prevention, 2014) In 2003 the World Health Organization estimated a global lifetime prevalence of 16% The economic burden of MDD in the United States in the year 2000 was estimated to be 83.1 billion dollars: with 26.1 billion dollars (31%) directly related to medical costs, 5.4 billion dollars (7%) related to suicide, 51.5 billion dollars (62%) due to workplace costs including absenteeism and reduced productivity 5

6 Diagnosis of major depression Based on the DSM-V At least 5 out of 9 symptoms during the same period of two weeks Diagnosis of major depression Hamilton Rating Scale for Depression At least 5 symptoms during the same period of two weeks 6

7 Pathophysiology of depression Different mechanisms responsible for the occurrence of MDD Monoamine neurotransmission HPA axis dysregulation and the stress response Inflammation Reduced neurogenesis and neuroplasticity Interaction between stress, inflammation, and neurogenesis Stress and depression From Raison et al., TRENDS in Immunology Vol.27 No.1 January 2006 Interaction between stress, inflammation, and neurogenesis 7

8 Stress and depression Physiological response Stress Pathological response Vulnerability Stress and depression Stress Vulnerability Sustained or repetitive stress in adulthood may trigger maladaptive changes in some individuals. It acts as a trigger for mechanisms that leave predisposed individuals at increased risk of illness. 8

9 Allostasis Allostatic responses are those physiological changes that occur in response to environmental perturbations. Environmtal stimuli Internal stimuli Homeostasis They represent an important positive role in helping an organism adapt to a changing environment Allostasis Homeostasis Constant or oscillating set point Physiologic equilibrium No or little anticipation of demand No adjustment base on history Adjustment carries no price No pathology Allostasis Changing set point Compensated equilibrium Extensive anticipation of demand Adjustment based on history Adjutment and accomodation carry a price (allostatic load) Potentially leads to pathology Allostasis = the active process by which the body responds to daily events and maintains homeostasis «Stability through change» 9

10 Allostasis From McEwen. Physiol Rev 87: , 2007 Central role of the brain in the allostasis and the behavioral and physiological response to stressors Allostasis and allostatic load Stress Response Stress Reaction Allostatic load refers to the wear and tear that result from either exaggerated stress or from inefficient management of allostasis. 10

11 Allostasis and allostatic load Four types of allostatic load From McEwen. Physiol Rev 87: , 2007 Vulnerability to disease Allostasis and allostatic load Proper functioning of the stress and glucocorticoid system is critical for normal brain function but excessive and long-term activation of this system can lead to disease 11

12 Allostasis and allostatic load Anatomical alterations in the hippocampus Autoradiogram shows uptake and retention of [3H]corticosterone by From McEwen et al.,. nature neuroscience VOLUME 18 NUMBER 10 OCTOBER Alteration of synaptic plasticity in the hippocampus Acceleration of aging process Allostasis and allostatic load Development of long-term vulnerability Initial equilibrium (Homeostasis) Desequilibrium (Symptoms) New equilibrium (Allostasis) Adaptation Stimulus a a Vulnerability Latent sensitization b Life events + Genotype Physiological response Stress b 12

13 Model of social defeat 1.Anticipation (30 mn) 2.Confrontation (15 mn) Alteration in the HPA axis Depression model (Becker et al., 2008 Molecular Psychiatry) Anxiety model (Becker et al., 2001 J. Neurosci.) 13

14 «Double hit» model DS Rest 7 days 4 days 1 month CMS 3 weeks 5days 57 days D 9 CMS procedure does not produce depressive-like behaviors 14

15 DS Rest 7 days 4 days 1 month CMS 3 weeks 5days 1month 57 days D 57 Forced-swimming test NR = Non responders R = Responders 60% 40% R NR Identification of two different populations after the CMS procedure 15

16 DS Rest 7 days 4 days 1 month CMS 3 weeks 5days 1month 57 days D 35 The level of serum BDNF is a biomarker of vulnerability to depression Long-term effects of stress on hippocampus SD induces sustained alteration of dendritic arborization in the hippocampus of responder animals 16

17 Effects of BDNF agonist 7,8-DHF icv D 35 D 57 BDNF agonist reverses SD-induced sustained alterations and vu of dendritic arborization in the hippocampus of responder animals DS Rest 7 days 4 days 1 month CMS 3 weeks 5days 1month 57 days HPA axis Circulating BDNF Dendritic arborisation Non sensitized HPA axis Porsolt - Circulating BDNF Dendritic arborisation Sensitized HPA axis Porsolt - Circulating BDNF Dendritic arborisation Non respondeurs HPA axis Porsolt - Ciruclating BDNF Dendritic arborisation Respondeurs HPA axis Porsolt + Circulating BDNF Dendritic arborisation Blugeot, Rivat et al., JNS,