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Kisspeptin is a physiological behavior regulator with therapeutic potential
S184
PNIRS meeting abstracts / Brain, Behavior, and Immunity 25 (2011) S179–S242
Although a pivotal role for inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), and nuclear factor (NF)kappaB, has been proposed during brain inflammation, the functional significance of their contribution to the induction of brain controlled sickness responses such as fever during infection and inflammation is unknown. AG490 a broadly used tyrosine kinase inhibitor has been shown to inhibit the STAT3and NFkappaB-signaling pathway. Thus, the purpose of the present study was to investigate the effect of AG490 on sickness behavior, fever and accompanying brain inflammation induced by systemic injection of lipopolysaccharide (LPS). Rats pretreated i.c.v. with AG490 1 h before the i.p. LPS-challenge showed modestly exaggerated fever, attenuated adipsia and no lethargy compared to LPS-controls receiving vehicle i.c.v. Using immunohistochemistry and realtime PCR we did not detect significant changes in brain activity of inflammatory transcription factors but did observe a significant decrease in hypothalamic anti-inflammatory IL-10 and increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA expression 8 h after LPS-injection in AG490 pretreated animals compared to solvent-LPS-controls. In summary, we have shown dissociation between the effects of central AG490 treatment on fever and sickness behavior, which appears to be related to reduced IL-10 and increased mPGES expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior without influencing the beneficial effects of fever during systemic inflammation. doi:10.1016/j.bbi.2011.07.020
18. How stress gets under the skin: Exaggerated threat appraisals as a mediator of the relationship between chronic stress and short leukocyte telomere length A. O’Donovan a,b, J. Tomiyama a, J. Lin a, E. Puterman a, M. Kemeny a, O. Wolkowitz a, N. Adler a, E.H. Blackburn a, E.S. Epel a a b
University of California, San Francisco, San Francisco, CA 94143, USA San Francisco VA Medical Center, USA
Chronic psychological stress has been associated with short telomere length, a marker and mechanism of biological aging. Stress appraisals are key determinants of emotional and biological responses to psychological stressors. To investigate if altered stress appraisals mediate the relationship between chronic stress and telomere length, we examined threat and challenge appraisals of a standardized acute stressor in female postmenopausal chronically stressed caregivers and matched controls (N = 54; M Age = 62). Participants completed selfreport measures of anticipatory and retrospective threat and challenge appraisals before and after standardized acute stressor tasks. Leukocyte telomere length was assessed with a quantitative polymerase chain reaction method. Compared with controls, caregivers had significantly higher odds of short telomere length (OR = 2.92, p < .05), higher anticipatory and retrospective threat appraisals (p < .05 for each), but similar challenge appraisals. Anticipatory threat appraisals were associated with increased odds of short telomere length independent of potential confounds and covariates including caregiver status and retrospective threat appraisals (OR = 4.32, p = .04). Furthermore, anticipatory threat appraisals appeared to partially mediate the relationship between caregiving stress and short telomere length, 95% CI [ 1.71, .01]. These findings provide the first replication of dementia caregiving effects on telomere length (Damjanovic et al., 2007), and suggest that chronically stressful life experience may influence telomere length by promoting exaggerated anticipatory threat responses to stress. doi:10.1016/j.bbi.2011.07.021
19. Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse S. Hasegawa-Ishii, S. Takei, A. Shimada 713-8 Kamiya, Aichi Human Service Center, Institute for Developmental Research, Kasugai, Aichi 480-0392, Japan Aging is a result of damage accumulation and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) exhibits accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescenceresistant control (SAMR1) strain. We recently demonstrated that microglia of young SAMP10 mice have degenerated processes similar to those in aged SAMR1 mice. We hypothesized that glia-neuron interactions neuroprotective against tissue injury are impaired in SAMP10 mice. We injected kainic acid (KA) into 3-month-old mice to induce hippocampal injury and studied cytokine-related gene upregulation on Day 3 by DNA microarray, quantitative real-time RT-PCR, and immunohistochemistry. Well-orchestrated cytokine-mediated glia-neuron immune networks occurred in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon-gamma stimulated astrocytes and thereby induced expression of CXCL10 and macrophage inflammatory protein-1alpha, and activated microglia produced granulocyte-macrophage colony-stimulating factor and osteopontin. CD44, an osteopontin receptor, was also strongly upregulated on neuronal dendrites and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice. On Day 30, SAMP10 but not SAMR1 mice exhibited hippocampal atrophy. Since the osteopontin-CD44 system is essential for neuroprotection, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration. doi:10.1016/j.bbi.2011.07.022
20. Kisspeptin is a physiological behavior regulator with therapeutic potential M. Cardon a, G.M. Lewitus a,b, M. Schwartz a a Weizmann Institute of Science, Neurobiology, PO Box 26, Rehovot 76100, USA b Departments of Neurology and Neurosurgery, Centre for Research in Neuroscience, The McGill University Health Center, Montreal, Quebec, Canada
Kisspeptin is an immune-regulated protein whose expression is down regulated in a neurodevelopmental animal model for schizophrenia. However, its role in the regulation of behavior has not been studied yet. In this study we explored the direct role of Kisspeptin in behavioral regulation, and its underlying mechanisms, as well as its therapeutic potential. We found that Kisspeptin is a physiological regulator of information processing, measured in paradigms of PPI; of learning and memory, measured by the Radial Arm Water Maze; and of depressive-like behavior, measured by tail suspension. The mechanisms underlying the effect of Kisspeptin on behavior regulation were found to involve GnRH, Neurotensin and BDNF. Finally, we demonstrated that Kisspeptin has antipsychotic activity, with positive effect on cognitive ability in mouse models of schizophrenia. Taken together, our results demonstrate a physiological role for Kisspeptin in behavioral regulation, with therapeutic potential. doi:10.1016/j.bbi.2011.07.023
PNIRS meeting abstracts / Brain, Behavior, and Immunity 25 (2011) S179–S242
Although a pivotal role for inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), and nuclear factor (NF)kappaB, has been proposed during brain inflammation, the functional significance of their contribution to the induction of brain controlled sickness responses such as fever during infection and inflammation is unknown. AG490 a broadly used tyrosine kinase inhibitor has been shown to inhibit the STAT3and NFkappaB-signaling pathway. Thus, the purpose of the present study was to investigate the effect of AG490 on sickness behavior, fever and accompanying brain inflammation induced by systemic injection of lipopolysaccharide (LPS). Rats pretreated i.c.v. with AG490 1 h before the i.p. LPS-challenge showed modestly exaggerated fever, attenuated adipsia and no lethargy compared to LPS-controls receiving vehicle i.c.v. Using immunohistochemistry and realtime PCR we did not detect significant changes in brain activity of inflammatory transcription factors but did observe a significant decrease in hypothalamic anti-inflammatory IL-10 and increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA expression 8 h after LPS-injection in AG490 pretreated animals compared to solvent-LPS-controls. In summary, we have shown dissociation between the effects of central AG490 treatment on fever and sickness behavior, which appears to be related to reduced IL-10 and increased mPGES expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior without influencing the beneficial effects of fever during systemic inflammation. doi:10.1016/j.bbi.2011.07.020
18. How stress gets under the skin: Exaggerated threat appraisals as a mediator of the relationship between chronic stress and short leukocyte telomere length A. O’Donovan a,b, J. Tomiyama a, J. Lin a, E. Puterman a, M. Kemeny a, O. Wolkowitz a, N. Adler a, E.H. Blackburn a, E.S. Epel a a b
University of California, San Francisco, San Francisco, CA 94143, USA San Francisco VA Medical Center, USA
Chronic psychological stress has been associated with short telomere length, a marker and mechanism of biological aging. Stress appraisals are key determinants of emotional and biological responses to psychological stressors. To investigate if altered stress appraisals mediate the relationship between chronic stress and telomere length, we examined threat and challenge appraisals of a standardized acute stressor in female postmenopausal chronically stressed caregivers and matched controls (N = 54; M Age = 62). Participants completed selfreport measures of anticipatory and retrospective threat and challenge appraisals before and after standardized acute stressor tasks. Leukocyte telomere length was assessed with a quantitative polymerase chain reaction method. Compared with controls, caregivers had significantly higher odds of short telomere length (OR = 2.92, p < .05), higher anticipatory and retrospective threat appraisals (p < .05 for each), but similar challenge appraisals. Anticipatory threat appraisals were associated with increased odds of short telomere length independent of potential confounds and covariates including caregiver status and retrospective threat appraisals (OR = 4.32, p = .04). Furthermore, anticipatory threat appraisals appeared to partially mediate the relationship between caregiving stress and short telomere length, 95% CI [ 1.71, .01]. These findings provide the first replication of dementia caregiving effects on telomere length (Damjanovic et al., 2007), and suggest that chronically stressful life experience may influence telomere length by promoting exaggerated anticipatory threat responses to stress. doi:10.1016/j.bbi.2011.07.021
19. Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse S. Hasegawa-Ishii, S. Takei, A. Shimada 713-8 Kamiya, Aichi Human Service Center, Institute for Developmental Research, Kasugai, Aichi 480-0392, Japan Aging is a result of damage accumulation and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) exhibits accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescenceresistant control (SAMR1) strain. We recently demonstrated that microglia of young SAMP10 mice have degenerated processes similar to those in aged SAMR1 mice. We hypothesized that glia-neuron interactions neuroprotective against tissue injury are impaired in SAMP10 mice. We injected kainic acid (KA) into 3-month-old mice to induce hippocampal injury and studied cytokine-related gene upregulation on Day 3 by DNA microarray, quantitative real-time RT-PCR, and immunohistochemistry. Well-orchestrated cytokine-mediated glia-neuron immune networks occurred in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon-gamma stimulated astrocytes and thereby induced expression of CXCL10 and macrophage inflammatory protein-1alpha, and activated microglia produced granulocyte-macrophage colony-stimulating factor and osteopontin. CD44, an osteopontin receptor, was also strongly upregulated on neuronal dendrites and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice. On Day 30, SAMP10 but not SAMR1 mice exhibited hippocampal atrophy. Since the osteopontin-CD44 system is essential for neuroprotection, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration. doi:10.1016/j.bbi.2011.07.022
20. Kisspeptin is a physiological behavior regulator with therapeutic potential M. Cardon a, G.M. Lewitus a,b, M. Schwartz a a Weizmann Institute of Science, Neurobiology, PO Box 26, Rehovot 76100, USA b Departments of Neurology and Neurosurgery, Centre for Research in Neuroscience, The McGill University Health Center, Montreal, Quebec, Canada
Kisspeptin is an immune-regulated protein whose expression is down regulated in a neurodevelopmental animal model for schizophrenia. However, its role in the regulation of behavior has not been studied yet. In this study we explored the direct role of Kisspeptin in behavioral regulation, and its underlying mechanisms, as well as its therapeutic potential. We found that Kisspeptin is a physiological regulator of information processing, measured in paradigms of PPI; of learning and memory, measured by the Radial Arm Water Maze; and of depressive-like behavior, measured by tail suspension. The mechanisms underlying the effect of Kisspeptin on behavior regulation were found to involve GnRH, Neurotensin and BDNF. Finally, we demonstrated that Kisspeptin has antipsychotic activity, with positive effect on cognitive ability in mouse models of schizophrenia. Taken together, our results demonstrate a physiological role for Kisspeptin in behavioral regulation, with therapeutic potential. doi:10.1016/j.bbi.2011.07.023