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Francesca Cirulli Section of Behavioural Neuroscience Istituto Superiore di Sanità Rome, Italy

Francesca Cirulli Section of Behavioural Neuroscience Istituto Superiore di Sanità Rome, Italy. IBNS 2013 - CONTRIBUTION OF EARLY ENVIRONMENTAL AND GENETIC SUSCEPTIBILITY TO BEHAVIOR RELATED TO ADULT PSYCHOPATHOLOGY.

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Francesca Cirulli Section of Behavioural Neuroscience Istituto Superiore di Sanità Rome, Italy

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  1. Francesca Cirulli Sectionof BehaviouralNeuroscience Istituto Superiore di Sanità Rome, Italy IBNS 2013 - CONTRIBUTION OF EARLY ENVIRONMENTAL AND GENETIC SUSCEPTIBILITY TO BEHAVIOR RELATED TO ADULT PSYCHOPATHOLOGY SEARCHING FOR EARLY DETERMINANTS OF EMOTIONAL REACTIVITY AND NEUROENDOCRINE RESPONSES TO STRESS IN ANIMAL MODELS

  2. Early adverse experiences in humans are associated with an increased risk for developing psychiatric disorders (Kaufman et al., 2000; McEwen, 2000; Heim and Nemeroff, 2001) According to a “two-hit” model, exposure to stress early on may sensitize the individual to stress at adulthood

  3. Biological mechanisms leading from stress exposure to psychiatric disorders have been only partially elucidated Stress can trigger a downregulation of neurotrophins, such as NGF and BDNF, which are critical regulators of brain circuits which regulate emotions

  4. In addition to stress-responsive systems, the expression of plasticity genes, such as those coding for neurotrophic factors, may be regulated epigenetically in the context of early life stress Chronic stressful conditions might sensitize limbic circuits to stress, decreasing brain plasticity and leading to greater susceptibility to psychopathology Cirulli et al. Neuroscience and Biobehavioral Reviews (2009)

  5. Data on maternal separation stress indicate a critical dysregulation of trophic factors expression in limbic brain areas involved in the etiopathogenesis of depression and schizophrenia as well as impaired response to chronic stress Roceri, Cirulli, Pessina, et al., Biol. Psych. (2004)

  6. Infant rearing condition of rhesus macaques Mother-reared

  7. Infant rearing condition of rhesus macaques Mother-reared Peer-reared

  8. Selective increases in BDNF in rhesus macaques in response to early adversity Cirulli et al., Psychoneuroendocrinology(2009)

  9. It has been suggested that the effects of stress on BDNF levels may depend upon a common variant on the BDNF gene (Val66Met; RS6265), the Met allele being associated with a decreased activity-dependent secretion of BDNF compared to the Val allele

  10. Genotype interacts with rearing condition in rhesus macaques moderating the effect of peer-rearing on circulating BDNF protein levels Cirulli et al., Psychoneuroendocrinology 2011

  11. Epigenetic modification of hippocampal BDNF DNA in adult rats in an animal model of post-traumatic stress disorder Roth et al. J Psychiatr Res J Psychiatr Research 2011 45:919-26. The expression of BDNF in rat prefrontal cortex can be reduced after early maltreatment, an effect due to increased promoter methylation

  12. POSEIDON: PRE-, PERI- AND POSTNATAL STRESS IN HUMAN & NON-HUMAN OFFSPRING: A TRANSLATIONAL APPROACH TO STUDY EPIGENETIC IMPACT ON DEPRESSION Main aim of this study is to relate changes in behavioral and neuroendocrine function resulting from prenatal stress to epigenetic changes in two candidate systems, the glucocorticoid receptors (GR) and the neurotrophinBDNFwhich are dysfunctional following early life stress

  13. Arrival Mating (24 h) Delivery (PND-0) 14 dd 21 dd Restraint stress 10 dd Pregnancy (21 dd) PND-1 (culling to 5 pups ♀/♂) PND-7 PND-21 (weaning 3 pups ♀/♂) PND-35 (SIT) PND-40 PND-60 (OF; EPM) PND-61 (FST day 1) PND-62 (FST day 2) (body weight) (body weight; 2 pups ♀/♂ sacrificed to collect blood, frontal cortex, hippocampus and hypothalamus) (body weight; 1 pup ♀/♂ sacrificed to collect frontal cortex, hippocampus and hypothalamus) • Sprague-Dawley female rats: n= 15 • Experimental groups: • Controls (C), n= 7 • Stress (S), n= 8 • - Offspring: n= 146 • - C, n= 68 (34 ♀/♂) • - S, n= 78 (40 ♀; 38 ♂) Restraint stress (3 daily sessions: 9:00 am, 12:00 am, 5:00 pm ± 2hrs under bright light for 45m) (Maccari et al., 2009)

  14. Control Prenatal Stress * 40 100 * 80 30 * 60 Duration (s) 20 40 10 20 0 0 0-5 5-10 10-15 15-20 20-25 25-30 Greater Social inactivityin the prenatal stress offspringindicatesgreater SOCIAL ANXIETY Time (min) SOCIAL INTERACTION TEST (PND-35)

  15. Control Prenatal Stress * 10 8 6 Duration (s) 4 2 0 0-5 5-10 10-15 15-20 20-25 25-30 Time blocks (min) Prenatally stressed rats are characterized by hyperactivity

  16. Reduced Social interest in prenatally stressed subjects * 4 3 Duration (s) 2 1 0 CC CS SC SS

  17. Higherlatency to enter in the open armsindicatesgreatergeneral anxietyin prenatally-stressedrats * 120 Control 100 Prenatal stress 80 Latency (s) 60 40 20 0

  18. Latency to first Sniffing, a measure of emotionality was significantly higher in control females, this effect was reverted after prenatal stress, suggesting a “feminization” of males * 25 20 F M 15 Latency to sniffing (s) 10 5 0 C S

  19. Differences in emotionality in prenatally-stressedsubjects indicate a rearrangement of neuroendocrine systemsinvolved in the response to stress

  20. Cirulli and Alleva, Front. Neuroendocrinology(2009)

  21. Adrenal response to stress 700 * 600 500 400 Corticosterone (ng/ml) 300 200 100 0 Control Prenatal Stress

  22. Cirulli and Alleva, Front. Neuroendocrinology(2009)

  23. Hypothalamic mRNA EXPRESSION LEVELS of the Glucocorticoid Receptor mRNAlevels (% of control) mRNAlevels (% of control) Control Prenatal stress

  24. Modifed from Cirulli and Alleva, Front. Neuroendocrinology(2009)

  25. Hypothalamic mRNA EXPRESSION LEVELS OF TOTAL BDNF mRNAlevels (% of control) mRNAlevels (% of control) Control Prenatal stress

  26. Hypothalamic mRNA EXPRESSION LEVELS OF BDNF LONG 3’-UTR (fast activity-dependent activation) mRNAlevels (% of control) mRNAlevels (% of control) Control Prenatal stress

  27. Increased hypothalamic BDNF levels which might contribute to enhance the neuroendocrine response to stress CORTICOSTERONE (ng/ml) Cirulli et al. Neuroscience and Biobehavioral Reviews (2010)

  28. Future studies • Characterize dynamic changes in BDNF secretion in response to stress • Methylation pattern of GR and BDNF and how this influences trafficking of GR and BDNF expression • Characterize other neuropeptides involved in social behavior: oxytocin and vasopressin

  29. Alessandra Berry, Veronica Bellisario, Sara Capoccia, Carla Raggi, Luca TommasoBonsignore, Pamela Panetta Department of Cell Biology and Neurosciences, IstitutoSuperiore di Sanità, Rome, Italy Marco A. Riva, AlessiaLuoni Department of Pharmacological Sciences, University of Milan Steven J. Suomi, Christina S. Barr Laboratory of Comparative Ethology, National Institute of Child Health and Human Development (NICHD), Bethesda, USA and Section of Comparative Behavioral Genomics, NIAAA, Rockville, MD 20852, USA Andreas Reif, Sabine Herterich, K. Peter Lesch Unit for MolecularPsychiatry (UMP) Dept. of Psychiatry and Psychotherapy, and Central Laboratory, Department of ClinicalBiochemistry and Pathobiochemistry, Julius-Maximilians-University Würzburg, Germany Luigi Aloe, Paola Tirassa Institute of Neurobiology, CNR, Rome, Italy ERA net-NEURON “Poseidon” 2010 FondazioneCariplo 2012

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