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S.04.04 The genetic basis of individual vulnerability to chronic stress: role of AMPA receptors
S.04. Hot Topics 1 nucleus of the amygdala (CeA) and locus coeruleus (LC) compared with vehicle-treated controls. In restraint-stressed rats, FLI was increased in all four regions by harmane but only in the CeA and LC by BU224. Dual labelling of FLI cells in the PVN revealed an increase in the number of corticotrophin releasing factor (CRF)-containing cells activated by BU224 and harmane in non-restraint rats. Several CRF neurons in the PVN were found to contain a1 -adrenoceptors and were densely surrounded by catecholaminergic axons and terminals. These data suggest that synthetic and endogenous imidazoline ligands increase neuronal activity in stress-responsive areas of the rat brain, effects which are preserved during exposure to acute psychological stress. These results provide a functional neuroanatomical framework which may explain the stimulatory effects of imidazoline ligands on basal and stress-induced neuronal and neuroendocrine activity. References [1] Finn et al., 2004 Imidazoline2 (I2 ) receptor- and a2 -adrenoceptormediated modulation of hypothalamic-pituitary-adrenal axis activity in control and restraint stressed rats. J Psychopharmacol. 18(1):47−53.
S.04.03 Exposure to an open-field induces c-Fos in a distributed anxiety-related system projecting to the basolateral amygdala M. Hale1 ° , A. Hay-Schmidt2 , J. Mikkelsen3 , B. Poulsen2 , A. Shekhar4 , C. Lowry1 . 1 University of Colorado, Department of Integrative Physiology, Boulder, USA; 2 The Panum Institute University of Copenhagen, Department of Neuroscience and Pharmacology, Copenhagen, Denmark; 3 University Hospital Rigshospitalet, Neurobiology Research Unit, Copenhagen, Denmark; 4 Indiana University School of Medicine, Department of Psychiatry and Pharmacology and Toxicology, Indianapolis, USA Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of brain structures including the basolateral amygdala (Singewald & Sharp, 2003). Our previous studies demonstrate that exposure of rats to an open-field results in a marked increase in c-Fos expression in the anterior part of the basolateral amygdaloid nucleus (BLA) compared to controls (Hale et al., 2006). The neural mechanisms underlying the anatomically specific effects on c-Fos expression in the BLA are not clear, however, it is likely that this reflects activation of specific afferent input to this region of the amygdala. In order to identify candidate brain regions mediating anxietyinduced activation of the BLA in rats, we used Cholera Toxin B subunit (CTb) as a retrograde tracer to identify neurons with direct afferent projections to this region in combination with c-Fos immunostaining to identify cells responding to exposure to an open-field arena in low-light (8−13 lux) conditions. Rats received a unilateral injection of 4% CTb into the BLA followed 7−11 days later by either exposure to an open-field in low-light conditions, brief handling or control conditions. Dual immunohistochemical staining for c-Fos and CTb revealed an increase in the percentage of c-Fos-immunopositive BLA-projecting neurons in open-fieldexposed rats compared with handled and control rats in the CA1 region of the ventral hippocampus, subiculum and lateral entorhinal cortex. These data are consistent with the hypothesis that exposure to the open-field arena activates an anxiety-related neuronal system with convergent input to the basolateral amygdaloid complex.
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References [1] Hale, M.W., Bouwknecht, J.A., Spiga, F., Shekhar, A., Lowry, C.A., 2006, Exposure to high- and low-light conditions in an open-field test of anxiety increases c-Fos expression in specific subdivisions of the rat basolateral amygdaloid complex. Brain Res Bull 71, 174–182. [2] Singewald, N., Salchner, P., Sharp, T., 2003, Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biol Psychiatry 53, 275–283
S.04.04 The genetic basis of individual vulnerability to chronic stress: role of AMPA receptors M.V. Schmidt1 ° , V. Sterlemann1 , D. Tr¨umbach2 , N. Datson3 , 1 Max-Planck-Institute P. Weber4 , F. Holsboer5 , M.B. M¨uller1 . of Psychiatry, Molecular Stress Physiology, Munich, Germany; 2 Helmholtz Zentrum M¨ unchen, Institute of Developmental Genetics, Neuherberg, Germany; 3 LACDR/LUMC, Medical Pharmacology, Leiden, The Netherlands; 4 Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, Munich, Germany; 5 Max-Planck-Institute of Psychiatry, Institute Director, Munich, Germany Chronic stress is widely regarded as a key risk factor for a variety of diseases, among which are affective disorders. Genetic predispositions are thought to interact with environmental demands such as chronic stress. Using a recently developed novel paradigm for chronic social stress in mice (Schmidt et al., 2007) we correlated individual differences in the persisting effects of chronic social stress on hypothalamic-pituitary-adrenal (HPA) function with gene expression changes in the hippocampus. One week after termination of the chronic stress procedure basal corticosterone secretion was markedly increased in the chronic stress group compared to controls. From the chronic stress group (n = 120) the animals with the lowest 20% corticosterone secretion were considered resistant to chronic stress exposure, while the animals with the highest 20% were considered vulnerable. After 4 more weeks of single housing, six animals of each subgroup were then selected for expression profiling in laser-microdissected dentate gyrus tissue. Analysis of regulated genes revealed differentially regulated AMPA receptor subunits, which might affect the susceptibility of an individual to chronic social stress. This hypothesis was tested in a second experiment, where animals were treated with the AMPA receptor enhancer LY451646 or vehicle during the last 4 weeks of chronic stress exposure. Enhanced AMPA receptor function in chronically stressed animals ameliorated the lasting effects of the chronic stress exposure on physiological, neuroendocrine and behavioural parameters. Our data suggest that differences in AMPA receptor function may underlie individual stress vulnerability and support AMPA receptor enhancers as novel potential antidepressants. References [1] Schmidt MV, Sterlemann V, Ganea K, Liebl C, Alam S, Harbich D, Greetfeld M, Uhr M, Holsboer F, M¨uller MB (2007) Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinology 32:417–429.
S.04.03 Exposure to an open-field induces c-Fos in a distributed anxiety-related system projecting to the basolateral amygdala M. Hale1 ° , A. Hay-Schmidt2 , J. Mikkelsen3 , B. Poulsen2 , A. Shekhar4 , C. Lowry1 . 1 University of Colorado, Department of Integrative Physiology, Boulder, USA; 2 The Panum Institute University of Copenhagen, Department of Neuroscience and Pharmacology, Copenhagen, Denmark; 3 University Hospital Rigshospitalet, Neurobiology Research Unit, Copenhagen, Denmark; 4 Indiana University School of Medicine, Department of Psychiatry and Pharmacology and Toxicology, Indianapolis, USA Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of brain structures including the basolateral amygdala (Singewald & Sharp, 2003). Our previous studies demonstrate that exposure of rats to an open-field results in a marked increase in c-Fos expression in the anterior part of the basolateral amygdaloid nucleus (BLA) compared to controls (Hale et al., 2006). The neural mechanisms underlying the anatomically specific effects on c-Fos expression in the BLA are not clear, however, it is likely that this reflects activation of specific afferent input to this region of the amygdala. In order to identify candidate brain regions mediating anxietyinduced activation of the BLA in rats, we used Cholera Toxin B subunit (CTb) as a retrograde tracer to identify neurons with direct afferent projections to this region in combination with c-Fos immunostaining to identify cells responding to exposure to an open-field arena in low-light (8−13 lux) conditions. Rats received a unilateral injection of 4% CTb into the BLA followed 7−11 days later by either exposure to an open-field in low-light conditions, brief handling or control conditions. Dual immunohistochemical staining for c-Fos and CTb revealed an increase in the percentage of c-Fos-immunopositive BLA-projecting neurons in open-fieldexposed rats compared with handled and control rats in the CA1 region of the ventral hippocampus, subiculum and lateral entorhinal cortex. These data are consistent with the hypothesis that exposure to the open-field arena activates an anxiety-related neuronal system with convergent input to the basolateral amygdaloid complex.
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References [1] Hale, M.W., Bouwknecht, J.A., Spiga, F., Shekhar, A., Lowry, C.A., 2006, Exposure to high- and low-light conditions in an open-field test of anxiety increases c-Fos expression in specific subdivisions of the rat basolateral amygdaloid complex. Brain Res Bull 71, 174–182. [2] Singewald, N., Salchner, P., Sharp, T., 2003, Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biol Psychiatry 53, 275–283
S.04.04 The genetic basis of individual vulnerability to chronic stress: role of AMPA receptors M.V. Schmidt1 ° , V. Sterlemann1 , D. Tr¨umbach2 , N. Datson3 , 1 Max-Planck-Institute P. Weber4 , F. Holsboer5 , M.B. M¨uller1 . of Psychiatry, Molecular Stress Physiology, Munich, Germany; 2 Helmholtz Zentrum M¨ unchen, Institute of Developmental Genetics, Neuherberg, Germany; 3 LACDR/LUMC, Medical Pharmacology, Leiden, The Netherlands; 4 Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, Munich, Germany; 5 Max-Planck-Institute of Psychiatry, Institute Director, Munich, Germany Chronic stress is widely regarded as a key risk factor for a variety of diseases, among which are affective disorders. Genetic predispositions are thought to interact with environmental demands such as chronic stress. Using a recently developed novel paradigm for chronic social stress in mice (Schmidt et al., 2007) we correlated individual differences in the persisting effects of chronic social stress on hypothalamic-pituitary-adrenal (HPA) function with gene expression changes in the hippocampus. One week after termination of the chronic stress procedure basal corticosterone secretion was markedly increased in the chronic stress group compared to controls. From the chronic stress group (n = 120) the animals with the lowest 20% corticosterone secretion were considered resistant to chronic stress exposure, while the animals with the highest 20% were considered vulnerable. After 4 more weeks of single housing, six animals of each subgroup were then selected for expression profiling in laser-microdissected dentate gyrus tissue. Analysis of regulated genes revealed differentially regulated AMPA receptor subunits, which might affect the susceptibility of an individual to chronic social stress. This hypothesis was tested in a second experiment, where animals were treated with the AMPA receptor enhancer LY451646 or vehicle during the last 4 weeks of chronic stress exposure. Enhanced AMPA receptor function in chronically stressed animals ameliorated the lasting effects of the chronic stress exposure on physiological, neuroendocrine and behavioural parameters. Our data suggest that differences in AMPA receptor function may underlie individual stress vulnerability and support AMPA receptor enhancers as novel potential antidepressants. References [1] Schmidt MV, Sterlemann V, Ganea K, Liebl C, Alam S, Harbich D, Greetfeld M, Uhr M, Holsboer F, M¨uller MB (2007) Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinology 32:417–429.