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CX3CR1 (fractalkine receptor)-deficient mice exhibit resilience to chronic unpredictable stress-induced depressive-like behavior and suppressed neurogenesis
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Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
outcomes were obtained from delivery records. We observed no significant associations between any of the sleep variables and MIF values. However, we did observe an association between MIF levels at T3 and risk of pregnancy complications, including hypertension, preterm labor/delivery, preeclampsia and PROM (b = 9.25, p = .033). MIF is thought to be an important determinant of the balance between pro- and anti-inflammatory processes and thus, may play an important role in pregnancy outcomes. However, the empirical evidence available regarding MIF in human pregnancy is limited. The null finding for sleep may be resultant of the normal compensatory/adaptation processes that occur following conception in order to protect the fetus. Additional work is required. http://dx.doi.org/10.1016/j.bbi.2015.06.053
Abstract # 1542 CX3CR1 (fractalkine receptor)-deficient mice exhibit resilience to chronic unpredictable stress-induced depressive-like behavior and suppressed neurogenesis N. Rimmerman, N. Schottlender, R. Yirmiya Psychology Department, Mount Scopus, The Hebrew University of Jerusalem, Jerusalem 91905, Israel We recently demonstrated that microglia undergo dynamic alterations in activation state during the development of chronic unpredictable stress (CUS)-induced depressive-like behavior in mice. Moreover, manipulations of microglial activation, which counteracted these dynamic alternations, reversed the depressive-like behavioral symptoms. Here, we sought to determine whether CX3CR1-deficient mice, which display a mildly activated microglial phenotype, show increased or decreased sensitivity to CUS-induced depressive-like behavior. Experiments were conducted on homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter, in which the CX3CR1 gene was functionally deleted, and their C57BL wild-type (WT) controls. We found that following five weeks of CUS exposure, microglia numbers were significantly reduced in the hippocampal dentate gyrus (DG), but not CA3 region, in both WT and CX3CR1-deficient mice. However, only CUS-exposed WT mice showed a significant reduction in microglia soma size compared to controls, indicating resistance of CX3CR1-deficient microglia to stress-induced morphological changes. In addition, only CUS-exposed WT mice showed reduced sucrose preference and impaired novel object recognition memory, suggesting that CX3CR1-deficient mice do not exhibit CUS-induced depressive-like behavior, and show superior memory functioning under stress. Finally, doublecortin immunostaining of the DG revealed that exposure to CUS decreased neurogenesis in WT but not in CX3CR1-deficient mice. We conclude that CX3CR1 deficiency, which is associated with a mildly activated microglial phenotype, confers resilience to CUS-induced microglial alterations, depressive-like behavior, a nd suppressed neurogenesis. http://dx.doi.org/10.1016/j.bbi.2015.06.054
Abstract # 1543 Sleep disruption and high risk of sleep apnea are independent predictors of increased disease activity in rheumatoid arthritis patients K. Scheuermaier a, R. Patel a, A. Solomon b, L. Dessein c, P. Dessein c
a Wits Sleep Laboratory, Brain Function Research Group, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, Gauteng 2193, South Africa b Department of Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, Johannesburg, South Africa c Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, P.O. Box 1012, Melville 2109, Johannesburg, South Africa
Sleep disruption has been shown to be associated with modifications in immune activation. In the auto-immune disorder rheumatoid arthritis (RA), increased disease activity is correlated with increased sleep disruption. In this study, we investigated whether sleep is an independent predictor of RA disease activity. Methods: We recruited 112 RA patients (94 females, average ageSD = 6012 years) from two rheumatology clinics in Johannesburg, South Africa. Each study participant filled in questionnaires assessing sleep quality (Pittsburgh Sleep Quality Index, PSQI) and risk of sleep apnea (high or low, using the Berlin Questionnaire, BQ); we also calculated the Disease Activity Score (DAS28) and collected erythrocyte sedimentation rate (ESR). We used DAS28 as the outcome variable. Results: Sleep disruption was high in this cohort (PSQI>5 = 79%, average PSQI scoreSD = 94) as well as disease activity (average DAS28SD = 3.81.8). In univariate analyses, higher DAS28 was associated with being female, higher ESR, PSQI score and scoring high risk of sleep apnea on the Berlin Questionnaire. In multivariate analyses, higher ESR (p<0.0001), PSQI score (p = 0.0144) and scoring high risk on the BQ (p = 0.0006) remained independent predictors of increased DAS28 score. Conclusion: Increased sleep disruption and scoring high risk of sleep apnea on the Berlin Questionnaire were independent predictors of increased rheumatoid arthritis disease activity when adjusting for ESR. This suggests that detecting/treating sleep disorders may be helpful in rheumatoid arthritis patients. http://dx.doi.org/10.1016/j.bbi.2015.06.055
Abstract # 1544 Microglia show sex-differences in gene expression patterns over development and following immune challenge: Relevance for sex-differences in neurodevelopmental disorders R. Hanamsagar a, J. Bolton a, M. Alter b, S. Bilbo a a
Duke University, 210 Research Dr, Box 91050, Durham, NC 27710, United States b University of Pennsylvania, Philadelphia, PA, United States Several neuropsychiatric disorders exhibit a marked sex difference in their prevalence and age of onset. Males are likely to have disorders that present early in childhood, including autism and learning disabilities. Females are often diagnosed with disorders that arise around/after puberty, including anxiety and depression. We have shown that early-life infection can adversely impact cognition specifically in adult males, correlating to increased number of amoeboid microglia observed in male hippocampus (HP) during early postnatal development. However, the functional differences between male and female microglia are unknown. We performed whole transcriptome profiling in microglia purified from HP of male and female C57BL/6 mice using Next Generation Sequencing. Microglia were collected at embryonic day 18 (E18), postnatal day 4 (P4), P14, and P60. Additionally, P60 animals were injected with either saline (SAL) or lipopolysaccharide (LPS, 330 lg/kg, i.p.) to induce a global inflammatory response. Principal component
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
outcomes were obtained from delivery records. We observed no significant associations between any of the sleep variables and MIF values. However, we did observe an association between MIF levels at T3 and risk of pregnancy complications, including hypertension, preterm labor/delivery, preeclampsia and PROM (b = 9.25, p = .033). MIF is thought to be an important determinant of the balance between pro- and anti-inflammatory processes and thus, may play an important role in pregnancy outcomes. However, the empirical evidence available regarding MIF in human pregnancy is limited. The null finding for sleep may be resultant of the normal compensatory/adaptation processes that occur following conception in order to protect the fetus. Additional work is required. http://dx.doi.org/10.1016/j.bbi.2015.06.053
Abstract # 1542 CX3CR1 (fractalkine receptor)-deficient mice exhibit resilience to chronic unpredictable stress-induced depressive-like behavior and suppressed neurogenesis N. Rimmerman, N. Schottlender, R. Yirmiya Psychology Department, Mount Scopus, The Hebrew University of Jerusalem, Jerusalem 91905, Israel We recently demonstrated that microglia undergo dynamic alterations in activation state during the development of chronic unpredictable stress (CUS)-induced depressive-like behavior in mice. Moreover, manipulations of microglial activation, which counteracted these dynamic alternations, reversed the depressive-like behavioral symptoms. Here, we sought to determine whether CX3CR1-deficient mice, which display a mildly activated microglial phenotype, show increased or decreased sensitivity to CUS-induced depressive-like behavior. Experiments were conducted on homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter, in which the CX3CR1 gene was functionally deleted, and their C57BL wild-type (WT) controls. We found that following five weeks of CUS exposure, microglia numbers were significantly reduced in the hippocampal dentate gyrus (DG), but not CA3 region, in both WT and CX3CR1-deficient mice. However, only CUS-exposed WT mice showed a significant reduction in microglia soma size compared to controls, indicating resistance of CX3CR1-deficient microglia to stress-induced morphological changes. In addition, only CUS-exposed WT mice showed reduced sucrose preference and impaired novel object recognition memory, suggesting that CX3CR1-deficient mice do not exhibit CUS-induced depressive-like behavior, and show superior memory functioning under stress. Finally, doublecortin immunostaining of the DG revealed that exposure to CUS decreased neurogenesis in WT but not in CX3CR1-deficient mice. We conclude that CX3CR1 deficiency, which is associated with a mildly activated microglial phenotype, confers resilience to CUS-induced microglial alterations, depressive-like behavior, a nd suppressed neurogenesis. http://dx.doi.org/10.1016/j.bbi.2015.06.054
Abstract # 1543 Sleep disruption and high risk of sleep apnea are independent predictors of increased disease activity in rheumatoid arthritis patients K. Scheuermaier a, R. Patel a, A. Solomon b, L. Dessein c, P. Dessein c
a Wits Sleep Laboratory, Brain Function Research Group, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, Gauteng 2193, South Africa b Department of Rheumatology, Charlotte Maxeke Johannesburg Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, Johannesburg, South Africa c Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, P.O. Box 1012, Melville 2109, Johannesburg, South Africa
Sleep disruption has been shown to be associated with modifications in immune activation. In the auto-immune disorder rheumatoid arthritis (RA), increased disease activity is correlated with increased sleep disruption. In this study, we investigated whether sleep is an independent predictor of RA disease activity. Methods: We recruited 112 RA patients (94 females, average ageSD = 6012 years) from two rheumatology clinics in Johannesburg, South Africa. Each study participant filled in questionnaires assessing sleep quality (Pittsburgh Sleep Quality Index, PSQI) and risk of sleep apnea (high or low, using the Berlin Questionnaire, BQ); we also calculated the Disease Activity Score (DAS28) and collected erythrocyte sedimentation rate (ESR). We used DAS28 as the outcome variable. Results: Sleep disruption was high in this cohort (PSQI>5 = 79%, average PSQI scoreSD = 94) as well as disease activity (average DAS28SD = 3.81.8). In univariate analyses, higher DAS28 was associated with being female, higher ESR, PSQI score and scoring high risk of sleep apnea on the Berlin Questionnaire. In multivariate analyses, higher ESR (p<0.0001), PSQI score (p = 0.0144) and scoring high risk on the BQ (p = 0.0006) remained independent predictors of increased DAS28 score. Conclusion: Increased sleep disruption and scoring high risk of sleep apnea on the Berlin Questionnaire were independent predictors of increased rheumatoid arthritis disease activity when adjusting for ESR. This suggests that detecting/treating sleep disorders may be helpful in rheumatoid arthritis patients. http://dx.doi.org/10.1016/j.bbi.2015.06.055
Abstract # 1544 Microglia show sex-differences in gene expression patterns over development and following immune challenge: Relevance for sex-differences in neurodevelopmental disorders R. Hanamsagar a, J. Bolton a, M. Alter b, S. Bilbo a a
Duke University, 210 Research Dr, Box 91050, Durham, NC 27710, United States b University of Pennsylvania, Philadelphia, PA, United States Several neuropsychiatric disorders exhibit a marked sex difference in their prevalence and age of onset. Males are likely to have disorders that present early in childhood, including autism and learning disabilities. Females are often diagnosed with disorders that arise around/after puberty, including anxiety and depression. We have shown that early-life infection can adversely impact cognition specifically in adult males, correlating to increased number of amoeboid microglia observed in male hippocampus (HP) during early postnatal development. However, the functional differences between male and female microglia are unknown. We performed whole transcriptome profiling in microglia purified from HP of male and female C57BL/6 mice using Next Generation Sequencing. Microglia were collected at embryonic day 18 (E18), postnatal day 4 (P4), P14, and P60. Additionally, P60 animals were injected with either saline (SAL) or lipopolysaccharide (LPS, 330 lg/kg, i.p.) to induce a global inflammatory response. Principal component