Project

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Stress and the Social Brain: The role of neuropeptides and synapse-specific neuroplasticity molecules

English title Stress and the Social Brain: The role of neuropeptides and synapse-specific neuroplasticity molecules
Applicant Sandi Carmen
Number 135710
Funding scheme Project funding (Div. I-III)
Research institution Laboratoire de Génétique Comportementale EPFL - SV - BMI
Institution of higher education EPF Lausanne - EPFL
Main discipline Genetics
Start/End 01.04.2011 - 31.03.2014
Approved amount 537'000.00
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All Disciplines (2)

Discipline
Genetics
Neurophysiology and Brain Research

Keywords (12)

Stress; Social Behavior; Glucocorticoids ; Learning and Memory; Aggression; Social Status ; Neuropeptides; Neuroligin; Polysialylation ; Neurexin; Plasticity; Rat

Lay Summary (English)

Lead
Lay summary

Stress is a potent modulator of brain function and behavior. Recent evidence indicates that stress can also have a major impact on social behaviors, but knowledge about the mediating mechanisms translating the effects of stress is scarce. In this project, we will use three rat stress models developed and/or characterized in our Lab, in which stress produces profound effects on different aspects of social behavior and social interactions. These models include: (i) Acute stress-induced amplification of memory for social hierarchy; (ii) Peri-puberty stress-induced potentation of male aggressive behavior in adulthood; and (iii) Chronic stress-induced social avoidance. In addition, we will use two mice models with null mutations for the enzymes -PST and STX- implicated in the polysialylation of the neural cell adhesion molecule (PSA-NCAM). Our former work has shown that these mice display altered social behaviors, as well as increased pathological aggression in conjunction with developmental alterations in PSA-NCAM expression. In addition to continuing exploring PSA-NCAM involvement, we aim to extend the search for molecular mediators of stress effects in social behaviors. Thus, we will investigate as well the role of ‘social’ neuropeptides oxytocin and vasopressin (due their well known involvement in the processing of social information under normal conditions) and the neuroplasticity molecules neuroligins and neurexins. The neuroligin-neurexin complex of adhesion molecules is broadly expressed in the central nervous system where they play a key role in or synapse-organizing activities for excitatory glutamatergic and inhibitory GABAergic synapses. Existing evidence suggest the implication of these molecules in autism and mental retardation.

We hypothesize that (i) the neuropeptidergic systems oxytocin and vasopressin, as well as molecules from the neurexin-neuroligin complex play a key role in stress-induced effects on social behavior; (ii) as well as on social alterations induced by deficits in the developmental expression of PSA-NCAM and their behavioral impact; (iii) stress and gonadal hormones are also important mediators of stress effects on social behavior and on the modulation of oxytocin and vasopressin systems and molecules from the neurexin-neuroligin complex (iv) targeting oxytocin and vasopressin systems and molecules from the neurexin-neuroligin complex will have a critical impact on stress-induced effects on social behaviors.

This project aims to test these hypotheses by using behavioral, genetic (mice mutations and adenovirus-associated genetic modifications), neurobiological, and neuropharmacological techniques, and by means of pursuing the following objectives:

1.To evaluate the modulation of OT and AVP systems and the neuroligin-neurexin complex molecules by stress-induced alterations in social behaviors.

2.To explore potential alterations in the expression of OT and AVP systems and the neuroligin-neurexin complex molecules in connection with changes in PSA-NCAM expression

3.To investigate the role of stress (glucocorticoids) and/or gonadal (testosterone) hormones on the modulation of OT and AVP systems and the neuroligin-neurexin complex molecules by stress and assessment of its link with alterations in social behaviors.

4.To explore the effectiveness of pharmacological and/or genetic interventions tackling OT and AVP systems and the neuroligin-neurexin complex molecules to prevent and/or to overcome stress-induced effects on social behaviors.

We expect to obtain important findings to critically contribute to the understanding of the mechanisms that underlie stress-induced alterations in social behavior. Stress produces a major burden in society by promoting social imbalance and impairing general and mental health. We expect our findings to provide important information that might eventually be the basis for the development of psychological and/or pharmacological therapeutic approaches.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Acute stress alters individual risk taking in a time-dependent manner and leads to anti-social risk
Bendahan Samuel, Goette Lorenz, Thoresen John C., Loued-Khenissi Leyla, Hollis Fiona, Sandi Carmen (2017), Acute stress alters individual risk taking in a time-dependent manner and leads to anti-social risk, in European Journal of Neuroscience, 45(7), 887-885.
Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice
Kohl Christine, Wang Xiao-Dong, Grosse Jocelyn, Fournier Céline, Harbich Daniela, Westerholz Sören, Li Ji-Tao, Bacq Alexandre, Sippel Claudia, Hausch Felix, Sandi Carmen, Schmidt Mathias V. (2015), Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice, in Psychoneuroendocrinology, 55, 128-143.
Stress and the social brain: behavioural effects and neurobiological mechanisms
Sandi Carmen, Haller József (2015), Stress and the social brain: behavioural effects and neurobiological mechanisms, in Nature Reviews Neuroscience, (16), 290-304.
Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress
Goette Lorenz, Bendahan Samuel, Thoresen John, Hollis Fiona, Sandi Carmen (2015), Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress, in Psychoneuroendocrinology, 54, 115-123.
Peripubertal stress-induced behavioral changes are associated with altered expression of genes involved in excitation and inhibition in the amygdala
Tzanoulinou Stamatina, Riccio Olivia, de Boer Matthijs, Sandi Carmen (2014), Peripubertal stress-induced behavioral changes are associated with altered expression of genes involved in excitation and inhibition in the amygdala, in Transl Psychiatry, (4), e410.
CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors
Veenit V., Riccio O., Sandi C. (2014), CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors, in J Psychiatr Res, 53, 1-7.
Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression.
van der Kooij M. A., Fantin M., Kraev I., Korshunova I., Grosse J., Zanoletti O., Guirado R., Garcia-Mompó C., Nacher J., Stewart M. G., Berezin V., Sandi C. (2014), Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression., in Neuropsychopharmacology, 39(5), 1148-1158.
Long-Term Behavioral Programming Induced by Peripuberty Stress in Rats Is Accompanied by GABAergic-Related Alterations in the Amygdala.
Tzanoulinou S., Garcia-Mompó C., Castillo-Gómez E., Veenit V., Nacher J., Sandi C. (2014), Long-Term Behavioral Programming Induced by Peripuberty Stress in Rats Is Accompanied by GABAergic-Related Alterations in the Amygdala., in Plos One, 9(4), e94666.
Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations
van der Kooij Michael A., Fantin Martina, Rejmak Emilia, Grosse Jocelyn, Zanoletti Olivia, Fournier Celine, Ganguly Krishnendu, Kalita Katarzyna, Kaczmarek Leszek, Sandi Carmen (2014), Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations, in Nature Communications, (5), 4995-4995.
Social deficits induced by peripubertal stress in rats are reversed by resveratrol
Poirier Guillaume L., Imamura Natsuko, Zanoletti Olivia, Sandi Carmen (2014), Social deficits induced by peripubertal stress in rats are reversed by resveratrol, in J Psychiatr Res, 57, 157-164.
A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory
Fantin Martina, van der Kooij Michael A., Grosse Jocelyn, Krummenacher Claude, Sandi Carmen (2013), A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory, in PLOS ONE, (2), e56897.
Female vulnerability to the development of depression-like behavior in a rat model of intimate partner violence is related to anxious temperament, coping responses and amygdala vasopressin receptor 1a expression
Poirier GL, Cordero MI, Sandi C (2013), Female vulnerability to the development of depression-like behavior in a rat model of intimate partner violence is related to anxious temperament, coping responses and amygdala vasopressin receptor 1a expression, in Frontiers in Behavioral Neuroscience, (35), 1-10.
Hippocampal Neuroligin-2 Overexpression Leads to Reduced Aggression and Inhibited Novelty Reactivity in Rats
Kohl Christine, Riccio Orbicia, Grosse Jocelyn, Zanoletti Olivia, Fournier Celine, Schmidt Mathias V., Sandi Carmen (2013), Hippocampal Neuroligin-2 Overexpression Leads to Reduced Aggression and Inhibited Novelty Reactivity in Rats, in PLOS ONE, (2), e56871.
Increased corticosterone in peripubertal rats leads to long-lasting alterations in social exploration and aggression
Veenit V, Cordero MI, Tzanoulinou S, Sandi C (2013), Increased corticosterone in peripubertal rats leads to long-lasting alterations in social exploration and aggression, in Frontiers in Behavioral Neuroscience, 26.
Long-term programming of enhanced aggression by peripuberty stress in female rats
Cordero MI., Ansermet F., Sandi C. (2013), Long-term programming of enhanced aggression by peripuberty stress in female rats, in Psychoneuroendocrinology, 38(11), 2758-2769.
Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression
Marquez C., Poirier G. L., Cordero M. I., Larsen M. H., Groner A., Marquis J., Magistretti P. J., Trono D., Sandi C. (2013), Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression, in TRANSLATIONAL PSYCHIATRY, (3), e216.
The interplay of conditional NCAM-knockout and chronic unpredictable stress leads to increased aggression in mice
Kohl Christina, Riccio Orbicia, Grosse Jocelyn, Zanoletti Olivia Fournier C Klampfl SM Schmidt MV Sandi C., Fournier Céline, Klampfl Sefanie M., Schmidt Mathias V., Sandi Carmen (2013), The interplay of conditional NCAM-knockout and chronic unpredictable stress leads to increased aggression in mice, in Stress, 16(6), 647-654.
Evidence for biological roots in the transgenerational transmission of intimate partner violence
Cordero M.I., Poirier G.L., Marquez C., Veenit V., Fontana F., Salehi B., Ansermet F., Sandi C. (2012), Evidence for biological roots in the transgenerational transmission of intimate partner violence, in Translational Psychiatry, 2(e106), 1-10.
Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity
Castro Jorge E., Diessler Shanaz, Varea Emilio, Marquez Cristina, Larsen Marianne H., Cordero M. Isabel, Sandi Carmen (2012), Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity, in PSYCHONEUROENDOCRINOLOGY, 37(8), 1209-1223.
Social memories in rodents: Methods, mechanisms and modulation by stress
van der Kooij Michael A., Sandi Carmen (2012), Social memories in rodents: Methods, mechanisms and modulation by stress, in NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, 36(7), 1763-1772.
Regulation of Nectin-3 in the hippocampus mediates chronic stress-induced behavioral alterations
Fantin M, Regulation of Nectin-3 in the hippocampus mediates chronic stress-induced behavioral alterations, in Nature Neuroscience.

Scientific events

Associated projects

Number Title Start Funding scheme
122697 State representation in reward based learning -- from spiking neuron models to psychophysics 01.01.2009 Sinergia
120791 Stress and social brain: a focus on the amygdala and the neuroplasticity molecule PSA/NCAM 01.04.2008 Project funding (Div. I-III)
145004 In vivo fast-scan cyclic voltammetry detection of neurotransmitters: A focus on dopamine 01.01.2013 R'EQUIP
122691 KRAB/KAP1 epigenetic regulation in the control of memory and emotional traits: from mice to humans. 01.12.2008 Sinergia

Abstract

Stress is a potent modulator of brain function and behavior. Recent evidence indicates that stress can also have a major impact on social behaviors, but knowledge about the mediating mechanisms translating the effects of stress is scarce. In this project, we will use three rat stress models developed and/or characterized in our Lab, in which stress produces profound effects on different aspects of social behavior and social interactions. These models include: (i) Acute stress-induced amplification of memory for social hierarchy; (ii) Peri-puberty stress-induced potentation of male aggressive behavior in adulthood; and (iii) Chronic stress-induced social avoidance. In addition, we will use two mice models with null mutations for the enzymes -PST and STX- implicated in the polysialylation of the neural cell adhesion molecule (PSA-NCAM). Our former work has shown that these mice display altered social behaviors, as well as increased pathological aggression in conjunction with developmental alterations in PSA-NCAM expression. In addition to continuing exploring PSA-NCAM involvement, we aim to extend the search for molecular mediators of stress effects in social behaviors. Thus, we will investigate as well the role of ‘social’ neuropeptides oxytocin and vasopressin (due their well known involvement in the processing of social information under normal conditions) and the neuroplasticity molecules neuroligins and neurexins. The neuroligin-neurexin complex of adhesion molecules is broadly expressed in the central nervous system where they play a key role in or synapse-organizing activities for excitatory glutamatergic and inhibitory GABAergic synapses. Existing evidence suggest the implication of these molecules in autism and mental retardation.We hypothesize that (i) the neuropeptidergic systems oxytocin and vasopressin, as well as molecules from the neurexin-neuroligin complex play a key role in stress-induced effects on social behavior; (ii) as well as on social alterations induced by deficits in the developmental expression of PSA-NCAM and their behavioral impact; (iii) stress and gonadal hormones are also important mediators of stress effects on social behavior and on the modulation of oxytocin and vasopressin systems and molecules from the neurexin-neuroligin complex (iv) targeting oxytocin and vasopressin systems and molecules from the neurexin-neuroligin complex will have a critical impact on stress-induced effects on social behaviors This project aims to test these hypotheses by using behavioral, genetic (mice mutations and adenovirus-associated genetic modifications), neurobiological, and neuropharmacological techniques, and by means of pursuing the following objectives: 1.To evaluate the modulation of OT and AVP systems and the neuroligin-neurexin complex molecules by stress-induced alterations in social behaviors.2.To explore potential alterations in the expression of OT and AVP systems and the neuroligin-neurexin complex molecules in connection with changes in PSA-NCAM expression3.To investigate the role of stress (glucocorticoids) and/or gonadal (testosterone) hormones on the modulation of OT and AVP systems and the neuroligin-neurexin complex molecules by stress and assessment of its link with alterations in social behaviors.4.To explore the effectiveness of pharmacological and/or genetic interventions tackling OT and AVP systems and the neuroligin-neurexin complex molecules to prevent and/or to overcome stress-induced effects on social behaviors. We expect to obtain important findings to critically contribute to the understanding of the mechanisms that underlie stress-induced alterations in social behavior. Stress produces a major burden in society by promoting social imbalance and impairing general and mental health. We expect our findings to provide important information that might eventually be the basis for the development of psychological and/or pharmacological therapeutic approaches.
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