The power of behaviour - to reveal vulnerability to stress related disorders and underlying neural mechanisms - Royal College of Psychiatrists
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3/27/2021 The power of behaviour to reveal vulnerability to stress‐related disorders and underlying neural mechanisms Carmen Sandi Brain Mind Institute EPFL Lausanne Switzerland Neuroscience Spring Conference 2021 Royal College of Psychiatrists, 26 March 2021 (Castro et al., 2012, Psychoneuroendocrinology) 1
3/27/2021 Chronic stress‐induced behavioral alterations & amygdala responsiveness: Modulation by trait anxiety Low anxious High anxious Isabel Cordero Individuals high in anxiety trait show more pronounced behavioral changes (increased depression‐like behaviors) after chronic stress & blunted amygdala ePhys responses (Sandi et al, EJN, 2008; Castro et al., Psychoneuroendocrinology 2012) Trait anxiety: key phenotype in vulnerability and resilience to stress Anxiety HA LA Low anxiety Individual differences Trait anxiety (Hollis et al., 2015, PNAS; van der Kooij et al., 2018, Mol. Psychiatry; Hollis et al., 2018, Neuropharmacology; Gebara et al., 2020, Mol Psychiatry) 2
3/27/2021 What cell types in the NAc are activated by social competition? D1‐containing medium spiny neurons (MSNs): ‐ Higher activation in LOW than in HIGH anxious rats NAc transient inactivation & NAc D1 antagonist reduce social dominance (Hollis et al., 2015 , PNAS; van der Kooij et al., 2018, Mol Psychiatry) HA rats have shorter dendrites and less spines in NAc MSNs than LA rats Confirmed for D1‐containing medium spiny neurons (MSNs) (Gebara et al., 2020, Mol. Psychiatry) 3
3/27/2021 HA rats display lower frequency of excitatory inputs onto medium spiny neurons (MSNs) in NAc – indicating poorer connectivity biocytin Simone Astori (Gebara et al., 2020, Mol. Psychiatry) Gene set enrichment analysis from GWAS microarray in NAc indicates mitochondrial differences between HA and LA (Hollis, van der Kooij et al., 2015, PNAS) 4
3/27/2021 Anxiety trait‐related differences in NAc mitochondrial function HA rats have: lower ETC respiration ‐ lower ATP ‐ higher ROS … that remains stable over time … and occurs in neurons, not in glia ‐ lower expression of Complex I and II proteins Mitochondrial function in NAc: Causally involved in the attainment of social dominance (Hollis, van der Kooij et al., 2015, PNAS; van der Kooij, Hollis et al., Mol Psychiatry, 2018; Gebara et al., 2020, Mol. Psychiatry) In the NAc, HA and LA rats differ in several mitochondria parameters Mt Density Mt Area Mt Coverage Mt‐ER Mt‐Mt Mitochondria ER (Gebara et al., 2020, Mol Psychiatry) 5
3/27/2021 Anxiety‐related differences in mitofusin‐2 (MFN2) expression in the NAc MFN2 MFN1 Drp1 OPA1 MFN2 (Gebara et al., 2020, Mol Psychiatry) Mitofusin 2 overexpression in the NAc of high anxious rats reverses: Behavioral phenotypes Elevated plus maze Saccharin preference Forced swim test Social competition Dendritic arborization Circuit connectivity (Gebara et al., 2020, Mol. Psychiatry) 6
3/27/2021 Role of variation in mitochondrial function in D1‐ or D2‐MSN in NAc for coping behaviors and underlying neural circuit engagement Francis and Lobo, 2017 Mitofusin‐2 in the nucleus accumbens: • is reduced in high anxiety • modulates mitochondrial and neuronal structure and function • and regulates locomotor behavior to stressful challenges & stress coping behaviors 7
3/27/2021 Is this phenomenon relevant for humans? 1H‐MRS in the human nucleus accumbens Anxiety trait associated with taurine levels in NAc (Strasser et al., 2019, Eur. Neuropsychopharmacol.; Strasser et al., 2020, Neuropsychopharmacology) 8
3/27/2021 The power of behaviour to reveal vulnerability to stress‐related disorders and underlying neural mechanisms Can we predict stress vulnerability from behavioral data in humans? Heart rate variability (HRV): An index of vulnerability to stress and disease A surrogate index of cardiac vagal break & autonomic nervous system (ANS) flexibility A measure of fluctuations over time in cardiac interbeat intervals due to the interaction of the two ANS branches: sympathetic (SNS) and parasympathetic (PNS) Low HRV values: associated with increased risk of developing psychopathologies, cardiovascular disorders and all‐cause mortality Stress‐related cardiovascular reactivity values elicited in laboratory settings: Outperform the predictive capacity of resting assessments Rather stable personal characteristics Modest prognostic value of stress reactivity studies based on exposure to non‐ecologically relevant laboratory stressors relying on a handful of variables Ambulatory cardiovascular studies more reliable but time‐consuming and not easy to standardize for interindividual comparisons (Rodrigues et al., 2020, Nat. Commun.) 9
3/27/2021 Machine learning model to predict HRV under threat / stress (Rodrigues et al., 2020, Nat. Commun.) Understanding the model & comparing its power to other measures (Rodrigues et al., 2020, Nat. Commun.) 10
3/27/2021 Validation and generalization of the model to predict HRV reactivity to stress (Rodrigues et al., 2020, Nat. Commun.) 11
3/27/2021 New computational methods for automatically estimating body postures (Sotocina et al., 2011; Finlayson et al., 2016; Defensor et al., 2012; Dolensek et al., 2020; Wolfe et al., 2011 ‐ From Ebbesen and Froemke, 2021) 12
3/27/2021 The power of behaviour to reveal vulnerability to stress‐related disorders and underlying neural mechanisms ACKNOWLEDGEMENTS Simone Astori Laia Morato Michael van der Kooij Joao Rodrigues COLLABORATORS Meltem Weger Fiona Hollis Marion Curdy Elias Gebara Thomas Larrieu Samuel Bendahan Gediminas Luksys (Univ Edinburgh) Sriparna Ghosal Rolf Gruetter (EPFL, Lausanne) Aurelie Papilloud Stephan Streuber Ioannis Zalachoras Lijing Xin (EPFL, Lausanne) Alexandre Bacq Erik Studer Eva Ramos Johan Auwerx (EPFL , Lausanne) Laura Lozano John Thoresen Haissa de Castro Graham Knott (EPFL , Lausanne) Damien Huzard Alina Strasser Silvia Monari Bernard Schneider (EPFL, Lausanne) Stamatina Tzanoulinou Isabelle Guillot Jun Huang Michael Herzog (EPFL, Lausanne) Vandana Veenit Jocelyn Grosse Alessandro Chioino David Atienza (EPFL, Lausanne) Sophie Walker Olivia Zanoletti Carles Canto (NIHS, Lausanne) Loredana Cumpana Cristina Berchio (Univ Geneva) Christoph Michel (Univ Geneva) Carla Nasca (Rockefeller, NY) Bruce McEwen (Rockefeller, NY) Martin Picard ( Columbia Univ, NY) Ron de Kloet (Leiden Univ) 13
3/27/2021 Thank you! 14
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