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130. Kynurenine 3-monooxygenase mediates inflammation-induced behavioral despair behavior in mice
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Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52
129. Blockade of L-type voltage dependent calcium channels or ryanodine receptors during chronic neuroinflammation improves spatial memory and reduces expression of inflammatory markers S.C. Hopp, S.E. Royer, H.M. D’Angelo, R.M. Kaercher, L. Adzovic, A.M. Crockett, G.L. Wenk The Ohio State University, Neuroscience, B91 Psychology Building, 1835 Neil Avenue, Columbus, OH 43210, USA Chronic neuroinflammation is a key component of Alzheimer’s disease and other neurodegenerative processes. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines as well as memory deficits. We have previously shown that neuroinflammation constitutively increases calcium-dependent immediate early gene expression which may underlie neuroinflammationinduced memory deficits. Enhancement of L-type voltage-dependent calcium channel (L-VDCC) and/or ryanodine receptor (RyR) activity may be related to neuroinflammation and lead to dysregulated increases of intracellular calcium and contribute to cognitive deficits. In order to examine the contribution of these two calcium channels to neuroinflammation-induced memory deficits, we pharmacologically targeted the L- VDCCs with nimodipine or the RyRs with dantrolene. To induce neuroinflammation, rats were treated with intraventricular infusion of lipopolysaccharide (LPS) for 28 days. We found that LPS-infused rats had significant memory deficits in the Morris water maze; this deficit was ameliorated by treatment with either nimodipine or dantrolene. We found significant increases in several inflammatory genes and microglia activation in the hippocampus of LPS-infused rats, both of which were reduced by treatment with either nimodipine or dantrolene, suggesting an anti-inflammatory effect of our pharmacological manipulations. Immediate early gene expression was also reduced to control levels in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function. Overall, these data suggest that calcium dysregulation via L-VDCCs and RyRs plays a crucial role in neuroinflammation-induced memory deficits. http://dx.doi.org/10.1016/j.bbi.2014.06.149
130. Kynurenine 3-monooxygenase mediates inflammationinduced behavioral despair behavior in mice J.M. Parrott a,b, L. Redus a, J.C. O’Connor a,b a
Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA b Center for Biomedical Neuroscience, San Antonio, TX, USA Patients suffering from chronic diseases are 5–10 times more likely to develop depression than the general population. Clinical data suggests that pro-inflammatory cytokines are important contributors to the pathogenesis of comorbid depression. Research into mechanisms potentially involved in this association have implicated the cytokine-inducible enzyme, indoleamine 2,3-dioxygenase (IDO). This is the rate limiting enzyme of the kynurenine pathway, and preclinical studies have demonstrated that IDO is critical for the development of inflammation-associated behavioral changes. Consistent with previous reports, we found that IDO expression is uniformly up-regulated in distinct brain regions, including amygdala, striatum, and hippocampus, following immune challenge. However, the expression profile of downstream kynurenine pathway enzymes was brain region-dependent. The metabolism of kynurenine by kynurenine 3-monooxygenase (KMO) yields neurotoxic metabolites, and previous work supports the hypothesis that an elevation in these metabolites during neuroinflammation precipitates the resultant
depression behaviors. To test this hypothesis, lipopolysaccharide (LPS) was administered intraperitoneally to wild-type (WT), KMO heterozygous (KMO +/ ) or KMO knockout (KMO / ) mice. Depressive-like behaviors were measured 24 h after LPS or saline treatment. LPS induced a decrease in sucrose preference (anhedonia) and in open field central area duration (anxiety-like behavior) in all three genotypes. However, KMO +/ and KMO / mice were protected from LPS-induced increase in immobility during the tail suspension test indicating that neurotoxic kynurenine metabolism is an important mediator of behavioral despair. http://dx.doi.org/10.1016/j.bbi.2014.06.150
131. Social isolation and gene expression tumor profiles in breast cancer patients J. Bower, S. Cole UCLA, Los Angeles, USA Psychosocial stress has long been hypothesized to play a role in breast cancer growth and progression. However, the association between stress and disease-relevant biological processes, particularly tumor characteristics, has not been examined in breast cancer patients. The current study examined the association between social isolation and gene expression tumor profiles in women with earlystage breast cancer. Ninety women were recruited from the UCLA tumor registry who had their tumors resected within the past 5 years and showed no current evidence of disease. Participants completed measures of stress and social isolation (Social Provisions Scale – Attachment Subscale) and consented to gene expression profiling of their banked tumors. Gene expression analyses comparing women reporting high vs. low social attachment identified >250 genes showing differential transcription between these groups (228 genes up-regulated in low social attachment group and 46 down-regulated). GOstat analyses of gene ontology annotations indicated upregulation of genes associated with translation/gene expression, metabolism, cell proliferation, stress response, cell differentiation, extracellular matrix, and wound response. Further, transcript origin analyses indicated up-regulation of gene expression profiles associated with M2 macrophages and mesenchymal cells in the low social attachment group (all ps < .01). Overall, this profile suggests activation of processes that may contribute to tumor growth and metastasis in women who are socially isolated. http://dx.doi.org/10.1016/j.bbi.2014.06.151
132. Inflammatory markers and depression in pregnancy: Results of the viral immunity in pregnancy study L.M. Osborne a, K. Fei b, T. Kraus b, T. Moran b, C. Monk a, R. Sperling b a Columbia University, Psychiatry, Division of Behavioral Medicine, 630 W. 168th Street, New York, NY 10032, USA b Mount Sinai School of Medicine, USA
Perinatal depression affects up to 15% of women in the developed world. Recent research indicates that immune dysregulation may play a role in its etiology, though many studies are based on onetime assessments of a few markers. We undertook a secondary data analysis of the Viral Immunity in Pregnancy Study (serial assays of 24 cytokines, n = 49). Forty-four percent of subjects were African American, 50% Latina; 57% overweight or obese; and 25% depressed at entry (Beck Depression Inventory 1A (BDI) score P10). Pearson correlation coefficients between BDI scores and those cytokine levels that were at or approaching significance were: 1st trimester, IL4 0.24 (p = 0.09), IL6 0.27 (p = 0.06); 2nd trimester, GMCSF 0.32 (p = 0.04),
Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52
129. Blockade of L-type voltage dependent calcium channels or ryanodine receptors during chronic neuroinflammation improves spatial memory and reduces expression of inflammatory markers S.C. Hopp, S.E. Royer, H.M. D’Angelo, R.M. Kaercher, L. Adzovic, A.M. Crockett, G.L. Wenk The Ohio State University, Neuroscience, B91 Psychology Building, 1835 Neil Avenue, Columbus, OH 43210, USA Chronic neuroinflammation is a key component of Alzheimer’s disease and other neurodegenerative processes. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines as well as memory deficits. We have previously shown that neuroinflammation constitutively increases calcium-dependent immediate early gene expression which may underlie neuroinflammationinduced memory deficits. Enhancement of L-type voltage-dependent calcium channel (L-VDCC) and/or ryanodine receptor (RyR) activity may be related to neuroinflammation and lead to dysregulated increases of intracellular calcium and contribute to cognitive deficits. In order to examine the contribution of these two calcium channels to neuroinflammation-induced memory deficits, we pharmacologically targeted the L- VDCCs with nimodipine or the RyRs with dantrolene. To induce neuroinflammation, rats were treated with intraventricular infusion of lipopolysaccharide (LPS) for 28 days. We found that LPS-infused rats had significant memory deficits in the Morris water maze; this deficit was ameliorated by treatment with either nimodipine or dantrolene. We found significant increases in several inflammatory genes and microglia activation in the hippocampus of LPS-infused rats, both of which were reduced by treatment with either nimodipine or dantrolene, suggesting an anti-inflammatory effect of our pharmacological manipulations. Immediate early gene expression was also reduced to control levels in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function. Overall, these data suggest that calcium dysregulation via L-VDCCs and RyRs plays a crucial role in neuroinflammation-induced memory deficits. http://dx.doi.org/10.1016/j.bbi.2014.06.149
130. Kynurenine 3-monooxygenase mediates inflammationinduced behavioral despair behavior in mice J.M. Parrott a,b, L. Redus a, J.C. O’Connor a,b a
Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA b Center for Biomedical Neuroscience, San Antonio, TX, USA Patients suffering from chronic diseases are 5–10 times more likely to develop depression than the general population. Clinical data suggests that pro-inflammatory cytokines are important contributors to the pathogenesis of comorbid depression. Research into mechanisms potentially involved in this association have implicated the cytokine-inducible enzyme, indoleamine 2,3-dioxygenase (IDO). This is the rate limiting enzyme of the kynurenine pathway, and preclinical studies have demonstrated that IDO is critical for the development of inflammation-associated behavioral changes. Consistent with previous reports, we found that IDO expression is uniformly up-regulated in distinct brain regions, including amygdala, striatum, and hippocampus, following immune challenge. However, the expression profile of downstream kynurenine pathway enzymes was brain region-dependent. The metabolism of kynurenine by kynurenine 3-monooxygenase (KMO) yields neurotoxic metabolites, and previous work supports the hypothesis that an elevation in these metabolites during neuroinflammation precipitates the resultant
depression behaviors. To test this hypothesis, lipopolysaccharide (LPS) was administered intraperitoneally to wild-type (WT), KMO heterozygous (KMO +/ ) or KMO knockout (KMO / ) mice. Depressive-like behaviors were measured 24 h after LPS or saline treatment. LPS induced a decrease in sucrose preference (anhedonia) and in open field central area duration (anxiety-like behavior) in all three genotypes. However, KMO +/ and KMO / mice were protected from LPS-induced increase in immobility during the tail suspension test indicating that neurotoxic kynurenine metabolism is an important mediator of behavioral despair. http://dx.doi.org/10.1016/j.bbi.2014.06.150
131. Social isolation and gene expression tumor profiles in breast cancer patients J. Bower, S. Cole UCLA, Los Angeles, USA Psychosocial stress has long been hypothesized to play a role in breast cancer growth and progression. However, the association between stress and disease-relevant biological processes, particularly tumor characteristics, has not been examined in breast cancer patients. The current study examined the association between social isolation and gene expression tumor profiles in women with earlystage breast cancer. Ninety women were recruited from the UCLA tumor registry who had their tumors resected within the past 5 years and showed no current evidence of disease. Participants completed measures of stress and social isolation (Social Provisions Scale – Attachment Subscale) and consented to gene expression profiling of their banked tumors. Gene expression analyses comparing women reporting high vs. low social attachment identified >250 genes showing differential transcription between these groups (228 genes up-regulated in low social attachment group and 46 down-regulated). GOstat analyses of gene ontology annotations indicated upregulation of genes associated with translation/gene expression, metabolism, cell proliferation, stress response, cell differentiation, extracellular matrix, and wound response. Further, transcript origin analyses indicated up-regulation of gene expression profiles associated with M2 macrophages and mesenchymal cells in the low social attachment group (all ps < .01). Overall, this profile suggests activation of processes that may contribute to tumor growth and metastasis in women who are socially isolated. http://dx.doi.org/10.1016/j.bbi.2014.06.151
132. Inflammatory markers and depression in pregnancy: Results of the viral immunity in pregnancy study L.M. Osborne a, K. Fei b, T. Kraus b, T. Moran b, C. Monk a, R. Sperling b a Columbia University, Psychiatry, Division of Behavioral Medicine, 630 W. 168th Street, New York, NY 10032, USA b Mount Sinai School of Medicine, USA
Perinatal depression affects up to 15% of women in the developed world. Recent research indicates that immune dysregulation may play a role in its etiology, though many studies are based on onetime assessments of a few markers. We undertook a secondary data analysis of the Viral Immunity in Pregnancy Study (serial assays of 24 cytokines, n = 49). Forty-four percent of subjects were African American, 50% Latina; 57% overweight or obese; and 25% depressed at entry (Beck Depression Inventory 1A (BDI) score P10). Pearson correlation coefficients between BDI scores and those cytokine levels that were at or approaching significance were: 1st trimester, IL4 0.24 (p = 0.09), IL6 0.27 (p = 0.06); 2nd trimester, GMCSF 0.32 (p = 0.04),