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Effects of early life stress on adult anxiety and learning and memory
S58
Abstracts
BMAL1 is rhythmically phosphorylated in the suprachiasmatic nucleus (SCN), the mammalian central pacemaker. CK2␣ activity pattern correlates with the circadian (circasemidian) pattern of cytoplasmic BMAL1 phosphorylation and subsequent nuclear accumulation. Gene silencing of CK2␣ or mutation of the highly conserved CK2-phosphorylation site in BMAL, Ser90, result in impaired nuclear BMAL1 accumulation and disruption of clock function. Notably, phosphorylation at Ser90 follows a rhythmic pattern. These findings reveal that circadian kinase CK2 is an essential regulator of the mammalian circadian system. doi:10.1016/j.neures.2009.09.150
O2-H2-6 Central AMPK contributes to homeostatic sleep regulation Hiroyoshi Sei, Sachiko Chikahisa, Noriyuki Shimizu, Nobuhiro Fujiki Dept. Integrative Physiol., The Univ. of Tokushima, Tokushima, Japan
O2-I1-3 Analysis of stress sensitivity observed in IL-1 receptor antagonist (IL-1ra) KO mice Chisato Wakabayashi 1,2 , Yoichiro Iwakura 2 1
National Institutes of Neuroscience, NCNP, Japan; Science, University of Tokyo, Japan
2
Institutes for Medical
In last congress, we had reported that IL-1 receptor antagonist (IL-1ra) KO mice was stress sensitive compared with littermate WT mice. Under non-stressed condition, IL-1ra KO mice showed anti-depressant-like phenotypes in TST and FST. Daily chronic immobilization stress caused anxiety-like phenotypes in IL-1ra KO mice but not in littermate WT mice. In contrast, chronic mild stressed WT mice showed anti-depressant-like phenotypes. This phenotype was same as which observed in non-stressed IL-1ra KO mice. Anti-depressant-like behavior was proved by the administration of adrenergic antagonist prazosin, yohimbine and propranolol. These results suggest all adrenergic receptor signaling affect to the induction of antidepressant-like behavior in IL-1ra KO mice. Very interestingly, the expression of one of adrenergic receptor in the hippocampus correlate to the anti-depressant-like behavior. We further evaluate whether there are correlation between the expression level of adrenergic receptors and behavioral abnormalities.
AMP-activated protein kinase (AMPK) is an energy-sensing molecular signal involved in glucose and lipid metabolism. The known interaction of sleep with energy metabolism led us to investigate the role of central AMPK in sleep homeostasis. Sleep deprivation (SD) for six hours increased the mRNA level of Ca2+ /calmodulin (CaM)-dependent protein kinase kinase beta (CaMKK2), an activator of AMPK, and p-AMPK protein in the hypothalamus. Central (ICV) injection of compound C (CC), an inhibitor of AMPK, suppressed EEG delta power during NREM sleep, and altered rebound responses of delta power in NREM sleep after SD. The CC treatment decreased mRNA expression of hypothalamic cycloxygenase 2, and neural and inducible nitric oxide synthase. Furthermore, AICAR, an AMPK enhancer, significantly increased low-frequency delta power compared to vehicle. These findings indicate a role for central AMPK in the regulation of NREM sleep, and a functional interaction between hypothalamic metabolism and sleep homeostasis.
O2-I1-4 The cutaneous afferents contributing to inhibitions of the sympathetic reflex elicited by excitation of unmyelinated C-afferent fibers in anesthetized rats Harumi Hotta 1 , Robert F. Schmidt 2 , Sae Uchida 1 , Nobuhiro Watanabe 1
doi:10.1016/j.neures.2009.09.151
2
O2-I1-1 Effects of early life stress on adult anxiety and learning and memory Mayumi Nishi, Mika Yagami, Naoko Kodama, Mitsuhiro Kawata Kyoto Pref. Univ. of Med., Japan Early childhood stress has been linked to psychopathology later in life. Animal studies are an efficient way to explore the long-term effects of early stress. This study used the maternal separation paradigm as a source of early stress. We investigated the effects of maternal separation (MS) (3 h/day on postnatal days 0–13) in C57BL/6 male mice on later adult behaviors. MS decreased anxiety in elevated plus maze, and impaired contextual memory in contextual fear conditioning (CFC) in adult mice and enriched environments reverse this effect. These findings suggest that this MS paradigm may induce a behavioral phenotype similar to that found in attention deficit hyperactivity disorder, and a favorable postnatal growth environment reverses this effect. We also examined the gene expression in the hippocampus by DNA microarrays. We will discuss alterations of gene expression caused by this MS paradigm. doi:10.1016/j.neures.2009.09.152
O2-I1-2 Molecular mechanism of pain induced by hydrogen peroxide Hiroshi Hosokawa 1 , Shingo Maegawa 1 , Koji Tajino 1 , Kiyoshi Matsumura 1,2 , Shigeo Kobayashi 1 1
Kyoto University, Japan; 2 Faculty of Information Science and Technology, Osaka Institute of Technology, Japan
Hydrogen peroxide contained in industrial products is also generated within the cells. Hydrogen peroxide (H2 O2 ) causes pain, but it has not been elucidated how H2 O2 ) activates sensory neurons in the pain pathway. Here we show that Transient Receptor Potential Ankyrin-1 (TRPA1), expressed by sensory neurons in the pain pathway, is a receptor for H2 O2 ). H2 O2 ) caused calcium influx in a subset of dorsal root ganglia neurons, which express TRPA1. In TRPA1-expressing HEK293 cells, H2 O2 ) induce Ca2+ influx by calcium imaging assay using Fura-2 and elicit nonselective cation currents by whole-cell clamp recordings. Inside-out patch-clamp recordings demonstrated that H2 O2 ) activated non-selective cation currents without any intracellular components. Cutaneous injection of H2 O2 ) did not elicit painful behavior in TRPA1 knockout mice, but not wildtype mice. These results indicate that TRPA1 is involved in sensation of pain caused by H2 O2 ). doi:10.1016/j.neures.2009.09.153
doi:10.1016/j.neures.2009.09.154
1
Dept. Auton. Nerv. Syst., Tokyo Metropol. Inst. Gerontol., Tokyo, Japan; Dept. Physiol., Univ. of Wurzburg, Germany
Previously we found that cutaneous touch (0.1 N) with a soft elastomer brush (1.1 cm in diameter) inhibits somatocardiac sympathetic C-reflex in anesthetized rats. The inhibitory effects were abolished by severing cutaneous nerves innervating where the touch stimulus was applied. The present study aimed to determine the type of receptors and afferent fibers responding to the touch stimulus. Single unitary afferent discharges in response to 10-min touch on the inner thigh were recorded from the saphenous nerve in anesthetized rats. We found that rapidly and slowly adapting low threshold mechanoreceptors with myelinated A- and A␦-afferents were excited during stimulation. In all afferents tested, mean discharge rate during stimulation was less than 3 Hz. These results indicate that low frequency inputs arising from low threshold cutaneous mechanoreceptors may contribute to inhibition of nociceptive transmission conveyed by unmyelinated C-afferents. doi:10.1016/j.neures.2009.09.155
O2-I1-5 Social isolation produces glucocorticoid-mediated disruption of cortical circuit formation Tomoyuki Miyazaki 1 , Kenkichi Takase 2 , Hirobumi Tada 1 , Dai Mitsushima 1 , Takuya Takahashi 1 1 Yokohama City University Graduate Sch. of Medicine, Department of Physiology, Japan; 2 Himeji Dokkyo University, Faculty of Pharmaceutical Sciences, Japan
Various mental stresses have variety of effects on brain functions. Social isolation, a long-lasting stressful event, early in life has profound lifelong influence on emotional and cognitive behaviors. However, the mechanism by which neonatal isolation affects synapses is poorly understood. We found that neonatal social isolation disrupted subsequent long-term potentiation and experience-dependent trafficking of AMPA receptors into synapses which resulted in the disruption of whisker-barrel map in the layer2/3 of barrel cortex and whisker dependent behavior. Furthermore, we showed that these effects were mediated by the stress hormone glucocorticoid. This indicates that prolonged stress induced by neonatal social isolation alters neuronal plasticity mechanisms and thus perturbs the initial establishment of a normal cortical circuit. doi:10.1016/j.neures.2009.09.156
Abstracts
BMAL1 is rhythmically phosphorylated in the suprachiasmatic nucleus (SCN), the mammalian central pacemaker. CK2␣ activity pattern correlates with the circadian (circasemidian) pattern of cytoplasmic BMAL1 phosphorylation and subsequent nuclear accumulation. Gene silencing of CK2␣ or mutation of the highly conserved CK2-phosphorylation site in BMAL, Ser90, result in impaired nuclear BMAL1 accumulation and disruption of clock function. Notably, phosphorylation at Ser90 follows a rhythmic pattern. These findings reveal that circadian kinase CK2 is an essential regulator of the mammalian circadian system. doi:10.1016/j.neures.2009.09.150
O2-H2-6 Central AMPK contributes to homeostatic sleep regulation Hiroyoshi Sei, Sachiko Chikahisa, Noriyuki Shimizu, Nobuhiro Fujiki Dept. Integrative Physiol., The Univ. of Tokushima, Tokushima, Japan
O2-I1-3 Analysis of stress sensitivity observed in IL-1 receptor antagonist (IL-1ra) KO mice Chisato Wakabayashi 1,2 , Yoichiro Iwakura 2 1
National Institutes of Neuroscience, NCNP, Japan; Science, University of Tokyo, Japan
2
Institutes for Medical
In last congress, we had reported that IL-1 receptor antagonist (IL-1ra) KO mice was stress sensitive compared with littermate WT mice. Under non-stressed condition, IL-1ra KO mice showed anti-depressant-like phenotypes in TST and FST. Daily chronic immobilization stress caused anxiety-like phenotypes in IL-1ra KO mice but not in littermate WT mice. In contrast, chronic mild stressed WT mice showed anti-depressant-like phenotypes. This phenotype was same as which observed in non-stressed IL-1ra KO mice. Anti-depressant-like behavior was proved by the administration of adrenergic antagonist prazosin, yohimbine and propranolol. These results suggest all adrenergic receptor signaling affect to the induction of antidepressant-like behavior in IL-1ra KO mice. Very interestingly, the expression of one of adrenergic receptor in the hippocampus correlate to the anti-depressant-like behavior. We further evaluate whether there are correlation between the expression level of adrenergic receptors and behavioral abnormalities.
AMP-activated protein kinase (AMPK) is an energy-sensing molecular signal involved in glucose and lipid metabolism. The known interaction of sleep with energy metabolism led us to investigate the role of central AMPK in sleep homeostasis. Sleep deprivation (SD) for six hours increased the mRNA level of Ca2+ /calmodulin (CaM)-dependent protein kinase kinase beta (CaMKK2), an activator of AMPK, and p-AMPK protein in the hypothalamus. Central (ICV) injection of compound C (CC), an inhibitor of AMPK, suppressed EEG delta power during NREM sleep, and altered rebound responses of delta power in NREM sleep after SD. The CC treatment decreased mRNA expression of hypothalamic cycloxygenase 2, and neural and inducible nitric oxide synthase. Furthermore, AICAR, an AMPK enhancer, significantly increased low-frequency delta power compared to vehicle. These findings indicate a role for central AMPK in the regulation of NREM sleep, and a functional interaction between hypothalamic metabolism and sleep homeostasis.
O2-I1-4 The cutaneous afferents contributing to inhibitions of the sympathetic reflex elicited by excitation of unmyelinated C-afferent fibers in anesthetized rats Harumi Hotta 1 , Robert F. Schmidt 2 , Sae Uchida 1 , Nobuhiro Watanabe 1
doi:10.1016/j.neures.2009.09.151
2
O2-I1-1 Effects of early life stress on adult anxiety and learning and memory Mayumi Nishi, Mika Yagami, Naoko Kodama, Mitsuhiro Kawata Kyoto Pref. Univ. of Med., Japan Early childhood stress has been linked to psychopathology later in life. Animal studies are an efficient way to explore the long-term effects of early stress. This study used the maternal separation paradigm as a source of early stress. We investigated the effects of maternal separation (MS) (3 h/day on postnatal days 0–13) in C57BL/6 male mice on later adult behaviors. MS decreased anxiety in elevated plus maze, and impaired contextual memory in contextual fear conditioning (CFC) in adult mice and enriched environments reverse this effect. These findings suggest that this MS paradigm may induce a behavioral phenotype similar to that found in attention deficit hyperactivity disorder, and a favorable postnatal growth environment reverses this effect. We also examined the gene expression in the hippocampus by DNA microarrays. We will discuss alterations of gene expression caused by this MS paradigm. doi:10.1016/j.neures.2009.09.152
O2-I1-2 Molecular mechanism of pain induced by hydrogen peroxide Hiroshi Hosokawa 1 , Shingo Maegawa 1 , Koji Tajino 1 , Kiyoshi Matsumura 1,2 , Shigeo Kobayashi 1 1
Kyoto University, Japan; 2 Faculty of Information Science and Technology, Osaka Institute of Technology, Japan
Hydrogen peroxide contained in industrial products is also generated within the cells. Hydrogen peroxide (H2 O2 ) causes pain, but it has not been elucidated how H2 O2 ) activates sensory neurons in the pain pathway. Here we show that Transient Receptor Potential Ankyrin-1 (TRPA1), expressed by sensory neurons in the pain pathway, is a receptor for H2 O2 ). H2 O2 ) caused calcium influx in a subset of dorsal root ganglia neurons, which express TRPA1. In TRPA1-expressing HEK293 cells, H2 O2 ) induce Ca2+ influx by calcium imaging assay using Fura-2 and elicit nonselective cation currents by whole-cell clamp recordings. Inside-out patch-clamp recordings demonstrated that H2 O2 ) activated non-selective cation currents without any intracellular components. Cutaneous injection of H2 O2 ) did not elicit painful behavior in TRPA1 knockout mice, but not wildtype mice. These results indicate that TRPA1 is involved in sensation of pain caused by H2 O2 ). doi:10.1016/j.neures.2009.09.153
doi:10.1016/j.neures.2009.09.154
1
Dept. Auton. Nerv. Syst., Tokyo Metropol. Inst. Gerontol., Tokyo, Japan; Dept. Physiol., Univ. of Wurzburg, Germany
Previously we found that cutaneous touch (0.1 N) with a soft elastomer brush (1.1 cm in diameter) inhibits somatocardiac sympathetic C-reflex in anesthetized rats. The inhibitory effects were abolished by severing cutaneous nerves innervating where the touch stimulus was applied. The present study aimed to determine the type of receptors and afferent fibers responding to the touch stimulus. Single unitary afferent discharges in response to 10-min touch on the inner thigh were recorded from the saphenous nerve in anesthetized rats. We found that rapidly and slowly adapting low threshold mechanoreceptors with myelinated A- and A␦-afferents were excited during stimulation. In all afferents tested, mean discharge rate during stimulation was less than 3 Hz. These results indicate that low frequency inputs arising from low threshold cutaneous mechanoreceptors may contribute to inhibition of nociceptive transmission conveyed by unmyelinated C-afferents. doi:10.1016/j.neures.2009.09.155
O2-I1-5 Social isolation produces glucocorticoid-mediated disruption of cortical circuit formation Tomoyuki Miyazaki 1 , Kenkichi Takase 2 , Hirobumi Tada 1 , Dai Mitsushima 1 , Takuya Takahashi 1 1 Yokohama City University Graduate Sch. of Medicine, Department of Physiology, Japan; 2 Himeji Dokkyo University, Faculty of Pharmaceutical Sciences, Japan
Various mental stresses have variety of effects on brain functions. Social isolation, a long-lasting stressful event, early in life has profound lifelong influence on emotional and cognitive behaviors. However, the mechanism by which neonatal isolation affects synapses is poorly understood. We found that neonatal social isolation disrupted subsequent long-term potentiation and experience-dependent trafficking of AMPA receptors into synapses which resulted in the disruption of whisker-barrel map in the layer2/3 of barrel cortex and whisker dependent behavior. Furthermore, we showed that these effects were mediated by the stress hormone glucocorticoid. This indicates that prolonged stress induced by neonatal social isolation alters neuronal plasticity mechanisms and thus perturbs the initial establishment of a normal cortical circuit. doi:10.1016/j.neures.2009.09.156