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P.2.001 Local inactivation of the G proteincoupled receptor 88 attenuates behavioural deficits elicited by neonatal administration of phencyclidine in rats
S31
Behavioural pharmacology
Lectures S.02.01 Stress and its impact on brain and behaviour: mechanisms and consequences, relevance to aggression and depression C. Sandi1 ° . 1 Ecole Polytechnique F´ed´erale de Lausanne (EPFL), Brain Mind Institute, Lausanne, Switzerland In addition to its well-known impact on cognitive function, stress has prominent effects in social behaviors. Epidemiological data in humans indicates that early life stress can have long-term consequences in individuals’ personality, including increased aggression and anti-social behaviors. Moreover, other stress-related pathological conditions, such as anxiety and depression are frequently associated with alterations in both the motivation and the actual way to interact with other conspecifics. Different animal models (maternal stress during the early postnatal period, peripubertal stress, chronic stress at adulthood) show that stress affects the nature of social interactions in rodents, their social motivation, dominance hierarchy, and aggression levels. Among the neural mechanisms identified to be altered by stress and linked to the deficits in social behaviors, we have identified changes in the expression of synaptic cell adhesion molecules and genes of the serotonin family (i.e., monoamine oxidase A, MAOA, whose epigenetic control is also affected by early stress), as well as in the dynamics of interactions between different brain regions, including amygdalamedial orbitofrontal circuit activity. Treatment with a MAOA inhibitor reverses anti-social behaviors induced by peripuberty stress. We also find evidence for a programing role of glucocorticoids and for a link between altered polysialylation of the neural cell adhesion molecule during development and pathological aggression. In a model of social hierarchy establishment in male rats, we have found that individuals scoring high in anxiety trait show a higher probability of becoming subordinate in a social contest between two males of otherwise equivalent characteristics. The same effect is observed when individuals interact upon the influence of stress. These findings highlight a strong effect of stress on the shaping of social and motivated behaviors and identify key neurobiological mechanisms as potential targets for the development of treatments.
Reference(s) [1] Marquez C., Poirier G., Cordero M.I., Larsen M.H., Groner A., Marquis J., Magistretti P., Trono D. and Sandi C.* (2013) Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Translational Psychiatry 3: e216. doi: 10.1038/tp.2012.144. [2] Veenit V., Cordero M.I., Tzanoulinou S. and Sandi C.* (2013) Increased corticosterone in peripubertal rats leads to long-lasting alterations in social exploration and aggression. Frontiers in Behavioral Neuroscience 7:26. doi: 10.3389/fnbeh.2013.00026. [3] Kohl C., Riccio O., Grosse J., Zanoletti O., Fournier C., Schmidt M.V.* and Sandi C.* (2013) Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. PloS One 8(2): e56871.
Posters P.2.001 Local inactivation of the G proteincoupled receptor 88 attenuates behavioural deficits elicited by neonatal administration of phencyclidine in rats M. Ingallinesi1 ° , L. Le Bouil1 , N. Faucon Biguet1 , M.J. Millan2 , J. Mallet1 , C. Mannoury la Cour2 , R. Meloni1 . 1 Institut du Cerveau et de Moelle e´ pini`ere (ICM), Biotechnology and Biotherapy laboratory, Paris, France; 2 Institut de Recherches SERVIER (IDRS), Unit´e Recherche et D´ecouverte Neuroscience, Croissy-SurSeine, France Purpose of the study: The Gpr88 gene, which codes for a G protein-coupled orphan receptor, is highly and almost exclusively represented in the striatum. In this structure, the expression of Gpr88 is restricted to the projecting medium spiny neurons and is regulated by dopamine and glutamate neurotransmission [1], two key systems strongly implicated in the etiology of schizophrenia (SZ). Moreover, mice with the constitutive knock-out of Gpr88 exhibit SZ-like phenotypes such as disrupted sensorimotor gating, hypersensitivity to amphetamine and cognitive deficits [2,3]. Taken together these findings suggest that
S32
Behavioural pharmacology
Gpr88 may be implicated in the etiology of SZ. In order to further characterize the relevance of Gpr88 in SZ-related dysfunctions affecting the meso-cortico-striatal circuits, the Gpr88 expression has been knocked-down specifically in the nucleus accumbens (NAcc) in a neurodevelopmental rat model of SZ. Methods: To reproduce positive, negative and cognitive symptoms of SZ, newborn rats were treated on postnatal days 7, 9, and 11 with PCP (10 mg/kg; s.c.) or saline for control group. The knock-down of Gpr88 has been generated using a lentiviral vector co-expressing the emerald Green Fluorescent Protein (emGFP) gene as a marker and either a specific microRNA (miR) directed against Gpr88 (miR-Gpr88) or a control inactive miR (miR-cont). Lentiviral vectors (2 ml/side) were bilateral injected by stereotaxic surgery into the NAcc of adult rat, and their efficacy was evaluated by emGFP detection, laser capture microdissection-PCR analysis and ‘in situ’ hybridization. Thereafter, the effects of neonatal PCP and/or lentiviral-mediated knock-down of Gpr88 were assessed by amphetamine (2 mg/kg; i.p.)-induced locomotor activity (50 min) and by the social novelty discrimination (SND) test. The SND test evaluates the ability of an adult rat to discriminate a novel from a familiar juvenile rat, giving an index of selective attention (score 3 in normal conditions). Results: The neonatal PCP treatment induced in the adult rats an increase in amphetamine-induced locomotion (343±45m versus 228±18m in control group, P < 0.0005) and a reduction in SND score (score = 2.0 versus score = 5.1 in control group, P < 0.05). In emGFP-positive cells, the Gpr88 expression was abolished by the miRGpr88 but not the miR-cont. In the whole NAcc, the miR-Gpr88 reduced Gpr88 mRNA levels to 38±29% as compared to the miR-cont. The knock-down of Gpr88 in the NAcc significantly reduced the amphetamineinduced hyperlocomotion (miR-Gpr88 = 260±20m, miRcont = 343±45m, P < 0.05) and improved the SND deficit (miR-Gpr88 score = 3, miR-cont score = 2) induced by neonatal PCP treatment. Conclusions: This study demonstrates that local lentiviral-mediated gene knock-down is an effective strategy for exploring the role of central Gpr88 receptors. Indeed, we show that Gpr88 is implicated in SZ-associated behavior. Though further work is needed, Gpr88 receptors may represent a novel potential target for the treatment of this debilitating disorder. Reference(s) [1] Massart, R., Guillou, J-P., Mignon, V., Sokoloff, P., Diaz, J., 2009. Striatal GPR88 expression is confined to the whole projection neuron population and
is regulated by dopaminergic and glutamatergic afferents. European Journal of Neuroscience 30, 397– 414. [2] Logue, S., Grauer, SM., Paulsen, J., Graf, R., Taylor, N., Sung, MA., Zhang, L., Hughes, Z., Pulito, VL., Liu, F., Rosenzweig-Lipson, S., Brandon, NJ., Marquis, KL., Bate, B., Pausch, M., 2009. The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders? Molecular and cellular neurosciences 42, 438–447. [3] Quintana, A., Sanz, E., Wang, W., Storey, GP., Gule, AD., Wanat, MJ., Roller, BA., La Torre, A., Amieux, PS., McKnight, GS., Bamford, NS., Palmiter, RD., 2012. Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors. Nature neuroscience 15, 1547–1555.
P.2.002 Opposing effects of subtype-specific CRF receptor activation in the adBNST on maternal care and the stress axis in lactating rats S.M. Klampfl1 ° , D.S. Bayerl1 , O.J. Bosch1 . 1 University of Regensburg, Behavioural and Molecular Neuroscience, Regensburg, Germany The peripartum period is accompanied by physiological and psychological adaptations of the maternal brain. This highly sensitive system is maladapted in 20−30% of mothers, which develop postpartum mood disorders and show child neglect. One factor that contributes evidently to such dysregulations is the corticotropinreleasing factor (CRF) [1]. We recently showed in lactating rats that central activation of CRF receptors (CRF-R1/2) impairs maternal behavior [2]. This effect could be assigned predominantly to CRF-R2 in the posterior bed nucleus of the stria terminalis (pBNST) (unpublished). The BNST represents a central relay station particularly in the stress response and its subnuclei often exert opposing functions. Thus, we hypothesized that activation of CRF-R in another functional part of the BNST, i.e. the anterior dorsal BNST (adBNST), modulates maternal behavior and hypothalamo–pituitary–adrenal (HPA) axis activity different from the pBNST in lactating rats. We administered specific agonists (CRF-R1: h/rCRF; CRF-R2: Stresscopin) or antagonists (CRF-R1: CP154,526; CRF-R2: Astressin-2B) via acute bilateral microinjections into the adBNST of early lactating rats. Afterwards, we observed maternal care under basal and stressful conditions and assessed maternal motivation in
Behavioural pharmacology
Lectures S.02.01 Stress and its impact on brain and behaviour: mechanisms and consequences, relevance to aggression and depression C. Sandi1 ° . 1 Ecole Polytechnique F´ed´erale de Lausanne (EPFL), Brain Mind Institute, Lausanne, Switzerland In addition to its well-known impact on cognitive function, stress has prominent effects in social behaviors. Epidemiological data in humans indicates that early life stress can have long-term consequences in individuals’ personality, including increased aggression and anti-social behaviors. Moreover, other stress-related pathological conditions, such as anxiety and depression are frequently associated with alterations in both the motivation and the actual way to interact with other conspecifics. Different animal models (maternal stress during the early postnatal period, peripubertal stress, chronic stress at adulthood) show that stress affects the nature of social interactions in rodents, their social motivation, dominance hierarchy, and aggression levels. Among the neural mechanisms identified to be altered by stress and linked to the deficits in social behaviors, we have identified changes in the expression of synaptic cell adhesion molecules and genes of the serotonin family (i.e., monoamine oxidase A, MAOA, whose epigenetic control is also affected by early stress), as well as in the dynamics of interactions between different brain regions, including amygdalamedial orbitofrontal circuit activity. Treatment with a MAOA inhibitor reverses anti-social behaviors induced by peripuberty stress. We also find evidence for a programing role of glucocorticoids and for a link between altered polysialylation of the neural cell adhesion molecule during development and pathological aggression. In a model of social hierarchy establishment in male rats, we have found that individuals scoring high in anxiety trait show a higher probability of becoming subordinate in a social contest between two males of otherwise equivalent characteristics. The same effect is observed when individuals interact upon the influence of stress. These findings highlight a strong effect of stress on the shaping of social and motivated behaviors and identify key neurobiological mechanisms as potential targets for the development of treatments.
Reference(s) [1] Marquez C., Poirier G., Cordero M.I., Larsen M.H., Groner A., Marquis J., Magistretti P., Trono D. and Sandi C.* (2013) Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Translational Psychiatry 3: e216. doi: 10.1038/tp.2012.144. [2] Veenit V., Cordero M.I., Tzanoulinou S. and Sandi C.* (2013) Increased corticosterone in peripubertal rats leads to long-lasting alterations in social exploration and aggression. Frontiers in Behavioral Neuroscience 7:26. doi: 10.3389/fnbeh.2013.00026. [3] Kohl C., Riccio O., Grosse J., Zanoletti O., Fournier C., Schmidt M.V.* and Sandi C.* (2013) Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. PloS One 8(2): e56871.
Posters P.2.001 Local inactivation of the G proteincoupled receptor 88 attenuates behavioural deficits elicited by neonatal administration of phencyclidine in rats M. Ingallinesi1 ° , L. Le Bouil1 , N. Faucon Biguet1 , M.J. Millan2 , J. Mallet1 , C. Mannoury la Cour2 , R. Meloni1 . 1 Institut du Cerveau et de Moelle e´ pini`ere (ICM), Biotechnology and Biotherapy laboratory, Paris, France; 2 Institut de Recherches SERVIER (IDRS), Unit´e Recherche et D´ecouverte Neuroscience, Croissy-SurSeine, France Purpose of the study: The Gpr88 gene, which codes for a G protein-coupled orphan receptor, is highly and almost exclusively represented in the striatum. In this structure, the expression of Gpr88 is restricted to the projecting medium spiny neurons and is regulated by dopamine and glutamate neurotransmission [1], two key systems strongly implicated in the etiology of schizophrenia (SZ). Moreover, mice with the constitutive knock-out of Gpr88 exhibit SZ-like phenotypes such as disrupted sensorimotor gating, hypersensitivity to amphetamine and cognitive deficits [2,3]. Taken together these findings suggest that
S32
Behavioural pharmacology
Gpr88 may be implicated in the etiology of SZ. In order to further characterize the relevance of Gpr88 in SZ-related dysfunctions affecting the meso-cortico-striatal circuits, the Gpr88 expression has been knocked-down specifically in the nucleus accumbens (NAcc) in a neurodevelopmental rat model of SZ. Methods: To reproduce positive, negative and cognitive symptoms of SZ, newborn rats were treated on postnatal days 7, 9, and 11 with PCP (10 mg/kg; s.c.) or saline for control group. The knock-down of Gpr88 has been generated using a lentiviral vector co-expressing the emerald Green Fluorescent Protein (emGFP) gene as a marker and either a specific microRNA (miR) directed against Gpr88 (miR-Gpr88) or a control inactive miR (miR-cont). Lentiviral vectors (2 ml/side) were bilateral injected by stereotaxic surgery into the NAcc of adult rat, and their efficacy was evaluated by emGFP detection, laser capture microdissection-PCR analysis and ‘in situ’ hybridization. Thereafter, the effects of neonatal PCP and/or lentiviral-mediated knock-down of Gpr88 were assessed by amphetamine (2 mg/kg; i.p.)-induced locomotor activity (50 min) and by the social novelty discrimination (SND) test. The SND test evaluates the ability of an adult rat to discriminate a novel from a familiar juvenile rat, giving an index of selective attention (score 3 in normal conditions). Results: The neonatal PCP treatment induced in the adult rats an increase in amphetamine-induced locomotion (343±45m versus 228±18m in control group, P < 0.0005) and a reduction in SND score (score = 2.0 versus score = 5.1 in control group, P < 0.05). In emGFP-positive cells, the Gpr88 expression was abolished by the miRGpr88 but not the miR-cont. In the whole NAcc, the miR-Gpr88 reduced Gpr88 mRNA levels to 38±29% as compared to the miR-cont. The knock-down of Gpr88 in the NAcc significantly reduced the amphetamineinduced hyperlocomotion (miR-Gpr88 = 260±20m, miRcont = 343±45m, P < 0.05) and improved the SND deficit (miR-Gpr88 score = 3, miR-cont score = 2) induced by neonatal PCP treatment. Conclusions: This study demonstrates that local lentiviral-mediated gene knock-down is an effective strategy for exploring the role of central Gpr88 receptors. Indeed, we show that Gpr88 is implicated in SZ-associated behavior. Though further work is needed, Gpr88 receptors may represent a novel potential target for the treatment of this debilitating disorder. Reference(s) [1] Massart, R., Guillou, J-P., Mignon, V., Sokoloff, P., Diaz, J., 2009. Striatal GPR88 expression is confined to the whole projection neuron population and
is regulated by dopaminergic and glutamatergic afferents. European Journal of Neuroscience 30, 397– 414. [2] Logue, S., Grauer, SM., Paulsen, J., Graf, R., Taylor, N., Sung, MA., Zhang, L., Hughes, Z., Pulito, VL., Liu, F., Rosenzweig-Lipson, S., Brandon, NJ., Marquis, KL., Bate, B., Pausch, M., 2009. The orphan GPCR, GPR88, modulates function of the striatal dopamine system: a possible therapeutic target for psychiatric disorders? Molecular and cellular neurosciences 42, 438–447. [3] Quintana, A., Sanz, E., Wang, W., Storey, GP., Gule, AD., Wanat, MJ., Roller, BA., La Torre, A., Amieux, PS., McKnight, GS., Bamford, NS., Palmiter, RD., 2012. Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors. Nature neuroscience 15, 1547–1555.
P.2.002 Opposing effects of subtype-specific CRF receptor activation in the adBNST on maternal care and the stress axis in lactating rats S.M. Klampfl1 ° , D.S. Bayerl1 , O.J. Bosch1 . 1 University of Regensburg, Behavioural and Molecular Neuroscience, Regensburg, Germany The peripartum period is accompanied by physiological and psychological adaptations of the maternal brain. This highly sensitive system is maladapted in 20−30% of mothers, which develop postpartum mood disorders and show child neglect. One factor that contributes evidently to such dysregulations is the corticotropinreleasing factor (CRF) [1]. We recently showed in lactating rats that central activation of CRF receptors (CRF-R1/2) impairs maternal behavior [2]. This effect could be assigned predominantly to CRF-R2 in the posterior bed nucleus of the stria terminalis (pBNST) (unpublished). The BNST represents a central relay station particularly in the stress response and its subnuclei often exert opposing functions. Thus, we hypothesized that activation of CRF-R in another functional part of the BNST, i.e. the anterior dorsal BNST (adBNST), modulates maternal behavior and hypothalamo–pituitary–adrenal (HPA) axis activity different from the pBNST in lactating rats. We administered specific agonists (CRF-R1: h/rCRF; CRF-R2: Stresscopin) or antagonists (CRF-R1: CP154,526; CRF-R2: Astressin-2B) via acute bilateral microinjections into the adBNST of early lactating rats. Afterwards, we observed maternal care under basal and stressful conditions and assessed maternal motivation in