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Histamine receptors and stress vulnerability
e398
Abstracts / Neuroscience Research 68S (2010) e335–e446
molecular basis of chronic stress and the onset of depression is largely unknown. Therefore, we investigated whether the alteration of the SGK1 mRNA expression level in the brain of chronically stressed mice plays a key role in the pathogenesis of depression. We have already revealed SGK1 mRNA upregulation in the brain of chronically stressed mice. However, it is difficult to explain the relationship between the onset of major depression and only SGK1 mRNA upregulation in the brain. Furthermore, the reception of an upstream signal of SGK1 from phosphatidylinositol 3-kinase is well characterized, but the downstream targets of SGK1 in the brain are barely known. Therefore, in order to investigate the role of SGK1 in the brain after exposure to stressful events, we attempted to identify novel interacting proteins of SGK1 in the human brain by using yeast two-hybrid screening with fulllength SGK1 as bait. We detected several synaptic vesicle proteins. Further, we examined whether these proteins interact with SGK1 in the neurons and analyzed the distribution of these synaptic vesicle mRNAs in the mouse brain. Hopefully, further studies will reveal candidate stress response mechanisms in the mouse brain. doi:10.1016/j.neures.2010.07.1763
P3-k14 Histamine receptors and stress vulnerability Kazuhiko Yanai 1 , Takeo Yoshikawa 1 , Eiko Sakurai 2 , Ayako Oikawa 1 , Fumito Naganuma 1 , Nobuyuki Okamura 1 1 Department of Pharmacology, Tohoku University Graduate School of Medicine 2 Faculty of Pharmacy, Iwaki Meisei University
Stress induces significant emotional changes and is related to disorders such as depression and anorexia nervosa. We reported that neuronal histamine is closely associated with acute and chronic stress responses. We propose that neuronal histamine is functioning so as to attenuate stressful responses. However, it is still unclear how the histamine receptors are involved in attenuating unfavorable stimuli of stress. The histamine receptor subtypes (H1, H2, H3, and H4) mediate these neuronal actions. In this study, we investigate the effects of histamine receptors on restraint stress induced behavioral changes in histamine receptors knockout (KO) and their wild type mice (WT). Histamine H1, H3 single receptors gene knockout (H1KO, H3KO), H1/H3 double receptors gene knockout (H1/H3-DKO), H1/H2/H3 triple receptors gene knockout (TKO) and WT mice were randomly divided into 3 groups. Mice were restrained in a mouse holder for 4 h during 5 consecutive days as physical stress group, and the other mice were set next to the restrained cages (as the psychological stress group). The control group was kept in a separate room. The body weight was decreased after subjecting to the restraint stress, especially in H1KO and TKO mice. After subjected to psychological stress, the initial response time in an open field was decreased in H1-KO and WT mice but not in H3-KO mice. The H1 receptors have an important role of modulating anxiety and stress. Blocked H3 receptor increases the release of neuronal histamine and released histamine binds to H1 receptor. In stressful conditions, histamine has a pivotal role in reducing stressful responses through the cross talk between H1 and H3 receptors. doi:10.1016/j.neures.2010.07.1764
P3-k15 Role of ghrelin signaling in the ventral tegmental area in binge-type overconsumption of a highly palatable sweet solution Megumi Tanibuchi , Yasunobu Yasoshima, Tadashi Inui, Tsuyoshi Shimura Div. of Behav. Physiol. Grad. Sch. Human Sci., Osaka University, Suita Excessive, binge-type consumption of a highly palatable taste substance is suggested to be an uncontrolled maladaptive non-homeostatic eating, i.e., hedonically motivated eating. One of gastrointestinal peptides, ghrelin, acts as an important regulator of homeostatic eating by actions on the hypothalamic feeding center. Recent studies suggest that ghrelin also stimulates food intake by acting on the ventral tegmental area (VTA) that is a part of the brain reward system. However, it has been not fully investigated whether ghrelin signaling in the VTA plays a role in uncontrolled non-homeostatic eating as binge-type overconsumption. To examine the issue, we examined the intake of 0.1 M sucrose solution induced by ghrelin infused into the VTA before and after behavioral training to develop binge-type overconsumption of a concentrated (0.5 M) sucrose solution in C57/BL6J male mice. The intake of 0.1 M sucrose induced by intra-VTA infusions of ghrelin was significantly increased after the experience of behavioral bingeing training; however, control mice without the training did not show increase of its intake in spite of the same infusion of ghrelin into the VTA. These results indicate that ghrelin
signaling in the VTA is enhanced after development of binge-type overconsumption, suggesting that neural change of the VTA induced by enhanced ghrelin signaling is one of potential neural substrates to develop binge-type overconsumption of highly palatable foods. doi:10.1016/j.neures.2010.07.1765
P3-k16 Effects of blockade of the dorsal gustatory route in the central gustatory pathways on binge-type overconsumption of a palatable sugar solution in mice Yasunobu Yasoshima , Megumi Tanibuchi, Tsuyoshi Shimura Div. of Behav. Physiol., Grad. Sch. Human Sci., Osaka University, Suita Intermittent access to a highly palatable taste substance leads to increase its intake, resulting in chronic hyperphagia and obesity. Brain mechanisms for overconsumption of a palatable sweetener are less known. To investigate the role of gustatory information processing in binge-type overconsumption, we examined the effects of lesions of gustatory and/or interoceptive areas in the insular cortex and of the thalamic gustatory area on binge-type overconsumption of a highly palatable, sweet taste solution in mice. Mice with the excitotoxic lesions of the gustatory and/or visceral areas of the insular cortex showed binge-type overconsumption of 0.5 M sucrose solution as control mice with sham lesions did. Mice with lesions of the gustatory thalamic area also showed binge-type overconsumption of the sweetener. Our results indicate that dysfunction of the cortical and thalamic gustatory areas did not attenuate binge-type overconsumption of a palatable taste substance, suggesting that the dorsal route from the gustatory thalamus to the insular cortex to encode taste quality and/or taste intensity in the central gustatory pathways is not always indispensable for development of binge-type overconsumption of palatable foods. doi:10.1016/j.neures.2010.07.1766
P3-k17 Effect of nutritional status on the expression of sweet taste receptor in rat hypothalamus Ke Chen 1 , Jianqun Yan 1,2 , Jinrong Li 1 , Qian Wang 1 , Bo Lu 1 1 Department of Physiology and Pathophysiology, Xian Jiaotong University School of Medicine, Xian, Shaanxi, P.R. China 2 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xian Jiaotong University School of Medicine, Xian, Shaanxi, P.R. China
Brain glucose sensing plays a critical role in the life and homeostasis of an organism. Previous studies have demonstrated that brain makes use of nutrient-sensing mechanisms similar with those known to operate in the taste bud, i.e., via sweet receptor T1R2/T1R3 and their downstream signaling molecules and have proven that the receptor located in the neurons of the hypothalamus is a candidate brain glucose sensor. To assess the possible functional roles of sweet taste-related signals in the brain and the relationship with nutritional state, we performed real-time PCR analyses on hypothalamic samples from high-fat diet-induced obese rats (HF) and chronically diet-restricted rats (CR), and compared the gene expression levels of sweet taste receptor T1R2/T1R3 and their associated downstream signaling molecules in these animals to those observed in rats that were fed ad libitum . Overall, we found that the mRNA expression of the taste receptor genes T1r2 in the hypothalamus was significantly lower (51%) in high-fat diet induced obese rats compared with that in the control rats (P = 0.001), indicating that taste receptor-related genes are sensitive to nutrient levels in the brain regions regulating energy homeostasis. These changes in expression levels seemed to be specific to the taste receptor genes T1r2. CR and HF rats showed non-significant changes in T1r3 and the down-stream proteins ␣-gustducin, PLC-2 and TRPM5 in the hypothalamus compared to normal animals. HF rats showed a 36% and 33% reduction while CR rats showed 11% and 42% increase in the expression of T1R3 and TRPM5, respectively. The results demonstrated that taste-related signaling elements play a role in sensing nutrients in the brain and their levels are regulated by the nutritional state of the animal, which suggests that taste-like signaling mechanisms in the brain might be involved in the central regulation of homeostatic processes. doi:10.1016/j.neures.2010.07.1767
Abstracts / Neuroscience Research 68S (2010) e335–e446
molecular basis of chronic stress and the onset of depression is largely unknown. Therefore, we investigated whether the alteration of the SGK1 mRNA expression level in the brain of chronically stressed mice plays a key role in the pathogenesis of depression. We have already revealed SGK1 mRNA upregulation in the brain of chronically stressed mice. However, it is difficult to explain the relationship between the onset of major depression and only SGK1 mRNA upregulation in the brain. Furthermore, the reception of an upstream signal of SGK1 from phosphatidylinositol 3-kinase is well characterized, but the downstream targets of SGK1 in the brain are barely known. Therefore, in order to investigate the role of SGK1 in the brain after exposure to stressful events, we attempted to identify novel interacting proteins of SGK1 in the human brain by using yeast two-hybrid screening with fulllength SGK1 as bait. We detected several synaptic vesicle proteins. Further, we examined whether these proteins interact with SGK1 in the neurons and analyzed the distribution of these synaptic vesicle mRNAs in the mouse brain. Hopefully, further studies will reveal candidate stress response mechanisms in the mouse brain. doi:10.1016/j.neures.2010.07.1763
P3-k14 Histamine receptors and stress vulnerability Kazuhiko Yanai 1 , Takeo Yoshikawa 1 , Eiko Sakurai 2 , Ayako Oikawa 1 , Fumito Naganuma 1 , Nobuyuki Okamura 1 1 Department of Pharmacology, Tohoku University Graduate School of Medicine 2 Faculty of Pharmacy, Iwaki Meisei University
Stress induces significant emotional changes and is related to disorders such as depression and anorexia nervosa. We reported that neuronal histamine is closely associated with acute and chronic stress responses. We propose that neuronal histamine is functioning so as to attenuate stressful responses. However, it is still unclear how the histamine receptors are involved in attenuating unfavorable stimuli of stress. The histamine receptor subtypes (H1, H2, H3, and H4) mediate these neuronal actions. In this study, we investigate the effects of histamine receptors on restraint stress induced behavioral changes in histamine receptors knockout (KO) and their wild type mice (WT). Histamine H1, H3 single receptors gene knockout (H1KO, H3KO), H1/H3 double receptors gene knockout (H1/H3-DKO), H1/H2/H3 triple receptors gene knockout (TKO) and WT mice were randomly divided into 3 groups. Mice were restrained in a mouse holder for 4 h during 5 consecutive days as physical stress group, and the other mice were set next to the restrained cages (as the psychological stress group). The control group was kept in a separate room. The body weight was decreased after subjecting to the restraint stress, especially in H1KO and TKO mice. After subjected to psychological stress, the initial response time in an open field was decreased in H1-KO and WT mice but not in H3-KO mice. The H1 receptors have an important role of modulating anxiety and stress. Blocked H3 receptor increases the release of neuronal histamine and released histamine binds to H1 receptor. In stressful conditions, histamine has a pivotal role in reducing stressful responses through the cross talk between H1 and H3 receptors. doi:10.1016/j.neures.2010.07.1764
P3-k15 Role of ghrelin signaling in the ventral tegmental area in binge-type overconsumption of a highly palatable sweet solution Megumi Tanibuchi , Yasunobu Yasoshima, Tadashi Inui, Tsuyoshi Shimura Div. of Behav. Physiol. Grad. Sch. Human Sci., Osaka University, Suita Excessive, binge-type consumption of a highly palatable taste substance is suggested to be an uncontrolled maladaptive non-homeostatic eating, i.e., hedonically motivated eating. One of gastrointestinal peptides, ghrelin, acts as an important regulator of homeostatic eating by actions on the hypothalamic feeding center. Recent studies suggest that ghrelin also stimulates food intake by acting on the ventral tegmental area (VTA) that is a part of the brain reward system. However, it has been not fully investigated whether ghrelin signaling in the VTA plays a role in uncontrolled non-homeostatic eating as binge-type overconsumption. To examine the issue, we examined the intake of 0.1 M sucrose solution induced by ghrelin infused into the VTA before and after behavioral training to develop binge-type overconsumption of a concentrated (0.5 M) sucrose solution in C57/BL6J male mice. The intake of 0.1 M sucrose induced by intra-VTA infusions of ghrelin was significantly increased after the experience of behavioral bingeing training; however, control mice without the training did not show increase of its intake in spite of the same infusion of ghrelin into the VTA. These results indicate that ghrelin
signaling in the VTA is enhanced after development of binge-type overconsumption, suggesting that neural change of the VTA induced by enhanced ghrelin signaling is one of potential neural substrates to develop binge-type overconsumption of highly palatable foods. doi:10.1016/j.neures.2010.07.1765
P3-k16 Effects of blockade of the dorsal gustatory route in the central gustatory pathways on binge-type overconsumption of a palatable sugar solution in mice Yasunobu Yasoshima , Megumi Tanibuchi, Tsuyoshi Shimura Div. of Behav. Physiol., Grad. Sch. Human Sci., Osaka University, Suita Intermittent access to a highly palatable taste substance leads to increase its intake, resulting in chronic hyperphagia and obesity. Brain mechanisms for overconsumption of a palatable sweetener are less known. To investigate the role of gustatory information processing in binge-type overconsumption, we examined the effects of lesions of gustatory and/or interoceptive areas in the insular cortex and of the thalamic gustatory area on binge-type overconsumption of a highly palatable, sweet taste solution in mice. Mice with the excitotoxic lesions of the gustatory and/or visceral areas of the insular cortex showed binge-type overconsumption of 0.5 M sucrose solution as control mice with sham lesions did. Mice with lesions of the gustatory thalamic area also showed binge-type overconsumption of the sweetener. Our results indicate that dysfunction of the cortical and thalamic gustatory areas did not attenuate binge-type overconsumption of a palatable taste substance, suggesting that the dorsal route from the gustatory thalamus to the insular cortex to encode taste quality and/or taste intensity in the central gustatory pathways is not always indispensable for development of binge-type overconsumption of palatable foods. doi:10.1016/j.neures.2010.07.1766
P3-k17 Effect of nutritional status on the expression of sweet taste receptor in rat hypothalamus Ke Chen 1 , Jianqun Yan 1,2 , Jinrong Li 1 , Qian Wang 1 , Bo Lu 1 1 Department of Physiology and Pathophysiology, Xian Jiaotong University School of Medicine, Xian, Shaanxi, P.R. China 2 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xian Jiaotong University School of Medicine, Xian, Shaanxi, P.R. China
Brain glucose sensing plays a critical role in the life and homeostasis of an organism. Previous studies have demonstrated that brain makes use of nutrient-sensing mechanisms similar with those known to operate in the taste bud, i.e., via sweet receptor T1R2/T1R3 and their downstream signaling molecules and have proven that the receptor located in the neurons of the hypothalamus is a candidate brain glucose sensor. To assess the possible functional roles of sweet taste-related signals in the brain and the relationship with nutritional state, we performed real-time PCR analyses on hypothalamic samples from high-fat diet-induced obese rats (HF) and chronically diet-restricted rats (CR), and compared the gene expression levels of sweet taste receptor T1R2/T1R3 and their associated downstream signaling molecules in these animals to those observed in rats that were fed ad libitum . Overall, we found that the mRNA expression of the taste receptor genes T1r2 in the hypothalamus was significantly lower (51%) in high-fat diet induced obese rats compared with that in the control rats (P = 0.001), indicating that taste receptor-related genes are sensitive to nutrient levels in the brain regions regulating energy homeostasis. These changes in expression levels seemed to be specific to the taste receptor genes T1r2. CR and HF rats showed non-significant changes in T1r3 and the down-stream proteins ␣-gustducin, PLC-2 and TRPM5 in the hypothalamus compared to normal animals. HF rats showed a 36% and 33% reduction while CR rats showed 11% and 42% increase in the expression of T1R3 and TRPM5, respectively. The results demonstrated that taste-related signaling elements play a role in sensing nutrients in the brain and their levels are regulated by the nutritional state of the animal, which suggests that taste-like signaling mechanisms in the brain might be involved in the central regulation of homeostatic processes. doi:10.1016/j.neures.2010.07.1767