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126. What have microglia got to do with it? New directions in the neurobiology of depression
PNIRS meeting abstracts / Brain, Behavior, and Immunity 25 (2011) S179–S242
study sought to demonstrate clear linkages between prenatal stress, biomarkers of stress and inflammation, and poor pregnancy outcome. Two hundred women were recruited from Denver Health Medical Center during their first trimester of pregnancy and followed until delivery. Early and late in pregnancy, women completed a series of psychosocial assessments and provided a blood sample. Assessments included measures of pregnancy-specific distress and support, overall stress, major life events, and self-efficacy. Serum levels of TNF-a, IL-6, IL-10, and CRP were measured via ELISA at each timepoint. Data on complications, delivery, and infant outcome were obtained through chart extraction. Elevated proinflammatory markers were related to lower social support, higher pregnancy-specific distress, and lower self-efficacy. Early elevations in TNF-a, IL-6, and CRP were predictive of preterm birth and increased frequency of complications overall. Similarly, higher distress and lower support were also related to more complications and preterm birth. This work provides some of the first data showing that stress and psychosocial factors are related to increases in stress and inflammation-related biomarkers, and that these increases, in turn, are associated with increased likelihood of pregnancy complications and premature delivery. doi:10.1016/j.bbi.2011.07.127
125. Peripheral lipopolysaccharide (LPS) injection causes amplified microglial activation, enhanced macrophage trafficking to the brain, and prolonged sickness behavior in socially defeated mice E.S. Wohleb a,b,c, A.M. Fenn a,c, J.P. Godbout c,d,e, J.F. Sheridan b,c,d a Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH 43210, USA b Oral Biology Section, USA c Molecular Virology, Immunology, and Medical Genetics, USA d Institute for Behavioral Medicine Research, USA e Center for Brain and Spinal Cord Injury, USA
Stress has a significant influence on immunity and behavior. Social Disruption Stress (SDR), a murine model of repeated social defeat, increased the inflammatory capacity of peripheral CD11b+ cells and reduced their sensitivity to anti-inflammatory regulation. Our recent findings indicate that SDR increased the inflammatory phenotype of brain CD11b+ cells (microglia (CD45low) and macrophages (CD45high)) through enhanced surface expression of Tolllike receptor-4 (TLR4) and CD14. To determine the consequence of the increased inflammatory phenotype of brain CD11b+ cells, control (HCC) and SDR mice were injected intraperitoneally with lipopolysaccharide (LPS). Enriched CD11b+ cells from SDR mice injected with LPS showed enhanced mRNA levels of inflammatory genes (IL-1(b), TNF-a, iNOS) compared to all groups. Flow cytometry confirmed that SDR increased CD14 and CX3CR1 on microglia compared to HCC, and microglia from SDR mice injected with LPS had significantly higher expression of CD14 and CX3CR1 compared to all groups. In addition, SDR enhanced macrophage trafficking and LPS markedly enhanced this effect. Furthermore, LPS caused enhanced expression of CD14, CD86, Ly6C, CCR2, and CX3CR1 on macrophages from SDR mice compared to all groups. The amplified neuroinflammatory response in SDR mice injected with LPS corresponded with decreased social exploratory behavior and extended weight loss. These findings demonstrate that SDR primes microglia and recruits macrophages to the brain leading to exaggerated neuroinflammation and behavioral impairments following an innate immune challenge. doi:10.1016/j.bbi.2011.07.128
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126. What have microglia got to do with it? New directions in the neurobiology of depression F.R. Walker, R. Tynan, T. Day, A. Ng, M. Hinwood University of Newcastle, School of Biomedical Sciences and Pharmacy, Newcastle, NSW 2308, Australia Recently it has become apparent that psychological stress can both structurally and functionally alter microglia, cells that are pivotal to the production of a neuroinflammatory state in the brain. The ability of stress to modulate microglial activity is of interest for two main reasons (a) stress is major risk factor in the emergence of depression and (b) depression appears to be characterised by enhanced levels of neuroinflammation. These two facts have led to the hypothesis that psychological stress may elicit changes in mood state and cognitive function by driving microglial mediated neuroinflammation. In investigating this hypothesis our research group, has found that chronic stress sufficient to induce an increase an anhedonic status and a decline in cognitive performance co-occurred with an increase in microglial activation within mood regulatory forebrain nuclei (notably the medial prefrontal cortex and amygdala). We have also found that targeting stress induced microglial activation with systematically administered anti-inflammatory agents improves stress induced cognitive decline. Moreover, our immunohistochemical investigations have identified that microglial activity is intimately linked with neuronal activity. Interestingly, stress induced changes in microglial activity were not clearly associated with markers of neurodegeneration. Indicating that the stress induced increase in microglial activation may be occurring via a non classical mechanism. Collectively, these findings may prove to be relevant in furthering our understanding of the neurobiology of depression. doi:10.1016/j.bbi.2011.07.129
127. Local and systemic glucocorticoid concentrations in a rat model of rheumatoid arthritis M.D. Taves, T. Bodnar, W. Yu, S. Huang, K.K. Soma, J. Weinberg University of British Columbia, Psychology, 2136 West Mall, Vancouver, BC, Canada V6T 1Z4 Glucocorticoids have powerful anti-inflammatory effects that mitigate damage caused by autoimmune disorders. In rheumatoid arthritis, inflamed joints have increased local expression of 11betahydroxysteroid dehydrogenase type 1 (11beta-HSD1), an enzyme that converts inactive glucocorticoid metabolites into active glucocorticoids. To determine whether upregulation of 11beta-HSD1 in arthritic joints leads to high local glucocorticoid levels, we measured corticosterone concentrations in blood, lymphoid organs, and forepaws of female Sprague-Dawley rats with adjuvant arthritis, a model of human rheumatoid arthritis. Rats from two different commercial breeders (Charles River and Harlan) were tested. Steroids were extracted using solid phase extraction and quantified with a sensitive and specific radioimmunoassay. We found that rats from the two commercial breeders exhibited different sensitivities to Complete Freund’s Adjuvant (CFA). Only Harlan rats developed arthritis after a low CFA dose, and a greater proportion of Harlan rats than of Charles River rats developed arthritis after a high CFA dose. Across all subjects, rats that developed arthritis had elevated corticosterone levels in plasma, whole blood, spleen, lymph nodes, and forepaws. These results suggest that local corticosterone synthesis in the joints is related to the degree of inflammation and plays a role in rheumatoid arthritis. Supported by NIH/NIMH R24 MH081797 and NIH/NIA-
study sought to demonstrate clear linkages between prenatal stress, biomarkers of stress and inflammation, and poor pregnancy outcome. Two hundred women were recruited from Denver Health Medical Center during their first trimester of pregnancy and followed until delivery. Early and late in pregnancy, women completed a series of psychosocial assessments and provided a blood sample. Assessments included measures of pregnancy-specific distress and support, overall stress, major life events, and self-efficacy. Serum levels of TNF-a, IL-6, IL-10, and CRP were measured via ELISA at each timepoint. Data on complications, delivery, and infant outcome were obtained through chart extraction. Elevated proinflammatory markers were related to lower social support, higher pregnancy-specific distress, and lower self-efficacy. Early elevations in TNF-a, IL-6, and CRP were predictive of preterm birth and increased frequency of complications overall. Similarly, higher distress and lower support were also related to more complications and preterm birth. This work provides some of the first data showing that stress and psychosocial factors are related to increases in stress and inflammation-related biomarkers, and that these increases, in turn, are associated with increased likelihood of pregnancy complications and premature delivery. doi:10.1016/j.bbi.2011.07.127
125. Peripheral lipopolysaccharide (LPS) injection causes amplified microglial activation, enhanced macrophage trafficking to the brain, and prolonged sickness behavior in socially defeated mice E.S. Wohleb a,b,c, A.M. Fenn a,c, J.P. Godbout c,d,e, J.F. Sheridan b,c,d a Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH 43210, USA b Oral Biology Section, USA c Molecular Virology, Immunology, and Medical Genetics, USA d Institute for Behavioral Medicine Research, USA e Center for Brain and Spinal Cord Injury, USA
Stress has a significant influence on immunity and behavior. Social Disruption Stress (SDR), a murine model of repeated social defeat, increased the inflammatory capacity of peripheral CD11b+ cells and reduced their sensitivity to anti-inflammatory regulation. Our recent findings indicate that SDR increased the inflammatory phenotype of brain CD11b+ cells (microglia (CD45low) and macrophages (CD45high)) through enhanced surface expression of Tolllike receptor-4 (TLR4) and CD14. To determine the consequence of the increased inflammatory phenotype of brain CD11b+ cells, control (HCC) and SDR mice were injected intraperitoneally with lipopolysaccharide (LPS). Enriched CD11b+ cells from SDR mice injected with LPS showed enhanced mRNA levels of inflammatory genes (IL-1(b), TNF-a, iNOS) compared to all groups. Flow cytometry confirmed that SDR increased CD14 and CX3CR1 on microglia compared to HCC, and microglia from SDR mice injected with LPS had significantly higher expression of CD14 and CX3CR1 compared to all groups. In addition, SDR enhanced macrophage trafficking and LPS markedly enhanced this effect. Furthermore, LPS caused enhanced expression of CD14, CD86, Ly6C, CCR2, and CX3CR1 on macrophages from SDR mice compared to all groups. The amplified neuroinflammatory response in SDR mice injected with LPS corresponded with decreased social exploratory behavior and extended weight loss. These findings demonstrate that SDR primes microglia and recruits macrophages to the brain leading to exaggerated neuroinflammation and behavioral impairments following an innate immune challenge. doi:10.1016/j.bbi.2011.07.128
S215
126. What have microglia got to do with it? New directions in the neurobiology of depression F.R. Walker, R. Tynan, T. Day, A. Ng, M. Hinwood University of Newcastle, School of Biomedical Sciences and Pharmacy, Newcastle, NSW 2308, Australia Recently it has become apparent that psychological stress can both structurally and functionally alter microglia, cells that are pivotal to the production of a neuroinflammatory state in the brain. The ability of stress to modulate microglial activity is of interest for two main reasons (a) stress is major risk factor in the emergence of depression and (b) depression appears to be characterised by enhanced levels of neuroinflammation. These two facts have led to the hypothesis that psychological stress may elicit changes in mood state and cognitive function by driving microglial mediated neuroinflammation. In investigating this hypothesis our research group, has found that chronic stress sufficient to induce an increase an anhedonic status and a decline in cognitive performance co-occurred with an increase in microglial activation within mood regulatory forebrain nuclei (notably the medial prefrontal cortex and amygdala). We have also found that targeting stress induced microglial activation with systematically administered anti-inflammatory agents improves stress induced cognitive decline. Moreover, our immunohistochemical investigations have identified that microglial activity is intimately linked with neuronal activity. Interestingly, stress induced changes in microglial activity were not clearly associated with markers of neurodegeneration. Indicating that the stress induced increase in microglial activation may be occurring via a non classical mechanism. Collectively, these findings may prove to be relevant in furthering our understanding of the neurobiology of depression. doi:10.1016/j.bbi.2011.07.129
127. Local and systemic glucocorticoid concentrations in a rat model of rheumatoid arthritis M.D. Taves, T. Bodnar, W. Yu, S. Huang, K.K. Soma, J. Weinberg University of British Columbia, Psychology, 2136 West Mall, Vancouver, BC, Canada V6T 1Z4 Glucocorticoids have powerful anti-inflammatory effects that mitigate damage caused by autoimmune disorders. In rheumatoid arthritis, inflamed joints have increased local expression of 11betahydroxysteroid dehydrogenase type 1 (11beta-HSD1), an enzyme that converts inactive glucocorticoid metabolites into active glucocorticoids. To determine whether upregulation of 11beta-HSD1 in arthritic joints leads to high local glucocorticoid levels, we measured corticosterone concentrations in blood, lymphoid organs, and forepaws of female Sprague-Dawley rats with adjuvant arthritis, a model of human rheumatoid arthritis. Rats from two different commercial breeders (Charles River and Harlan) were tested. Steroids were extracted using solid phase extraction and quantified with a sensitive and specific radioimmunoassay. We found that rats from the two commercial breeders exhibited different sensitivities to Complete Freund’s Adjuvant (CFA). Only Harlan rats developed arthritis after a low CFA dose, and a greater proportion of Harlan rats than of Charles River rats developed arthritis after a high CFA dose. Across all subjects, rats that developed arthritis had elevated corticosterone levels in plasma, whole blood, spleen, lymph nodes, and forepaws. These results suggest that local corticosterone synthesis in the joints is related to the degree of inflammation and plays a role in rheumatoid arthritis. Supported by NIH/NIMH R24 MH081797 and NIH/NIA-