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#109 Relationship between physiological stress indices and salivary cortisol level
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Abstracts / Brain, Behavior, and Immunity 19 (2005) e43–e74
#107 Indicators of innate immune system activity in humans increase with psychosocial stressor challenge: Major depressives vs. non-depressives Thaddeus W.W. Pace, Tanja M. Mletzko, Oyetunde Alagbe, Gerald J. Vogt, Fang Hu, Andrew H. Miller, Erica C. Bruce, Dominique L. Musselman, Charles B. Nemeroff, Christine M. Heim Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA Prior studies have demonstrated that acute stressor challenge increases plasma levels of proinflammatory cytokines such interleukin-6 (IL-6), and the number of natural killer (NK) cells in bulk peripheral blood mononuclear cells (PBMCs). In addition, acute stressor challenge has also been found to increase DNA binding activity of nuclear factor-jB (NF-jB) in bulk PBMCs. NF-jB is of interest because it is an important regulator of genes associated with immune system function. We report here changes in PBMC NF-jB DNA binding, plasma IL-6, and NK cell proportions in PBMCs as a result of challenge with the Trier Social Stressor Test (TSST) in clinically depressed (MDDs; n = 12) and non-depressed (NDs, n = 19) male participants (mean age 31). Plasma IL-6 was measured with an enzyme-linked immunosorbent assay (ELISA) (R&D Systems), NK cell numbers were determined via flow cytometry, and NF-jB DNA binding was measured with an ELISA-based kit built upon the consensus DNA sequence for NF-jB (Active Motif). On the whole, TSST challenge increased all three measures of innate immune function relative to baseline values. Although in this study MDDs did not have higher basal levels of plasma IL-6, NK cell numbers, or NF-jB binding relative to NDs, they did exhibit a greater increase in NF-jB binding and plasma IL-6 as a result of TSST challenge. Maximum plasma IL-6 was also significantly correlated with maximum NF-jB DNA binding. However, NK cell numbers did not differ between the groups during or after the stressor. These data suggest that major depressives may have an enhanced innate immune response to a psychosocial stressor measurable at the level of NF-jB. Such a increased response could be due to the lack of inhibitory effects normally exerted over innate immunity, such as those from endogenous glucocorticoids. Supported by NARSAD Young Investigator Award to CHM; MH058922-06 to CBN & AHM. doi:10.1016/j.bbi.2005.10.114
#108 The androgen, androstenediol, counter-regulates glucocorticoid-mediated suppression of inflammatory gene expression and accelerates wound repair David A. Padgett, Michael J. Farrow, Cynthia C. Head, John F. Sheridan The Institute for Behavioral Medicine Research, The Ohio State University, USA
Glucocorticoids (GC), which are elevated by stress, suppress cytokine responses during the inflammatory stage of wound healing. Suppression of inflammatory gene expression is associated with delayed closure of cutaneous wounds. Treatment of mice with the androgen, androstenediol (AED), restored cytokine responses in stressed animals and also accelerated wound closure. To determine a mechanism of action, these current experiments were designed to distinguish differences between AED and GC in regulating inflammatory gene expression. We hypothesized that AED would act as an agonist of the androgen receptor (AR), counter the anti-inflammatory influence of GC, and modulate NF-jB activity. To test this, RAW 264.7 macrophages were stimulated with LPS to induce inflammatory cytokine production. Changes in inflammatory gene transcription after treatment with dexamethasone (DEX) and/or AED were assessed using focused microarrays, real-time PCR and ELISA. A transcription factor binding assay was employed to determine differences in activation of NF-jB. The results demonstrated that AED counter-regulated DEX-induced suppression of multiple genes involved in inflammation including TLR-4 and TNF-a. AED also enhanced the quantity of transcriptionally active p65 which was suppressed by DEX treatment alone. The anti-glucocorticoid effects of AED were blocked by cyproterone acetate (an AR antagonist). These observations indicate that AED modulates the anti-inflammatory transcriptional influence of GC in an androgen receptor-dependent manner. Supported by MH56899 to DAP, T32DE014320 to MJF, and F30DE14304 to CCH. doi:10.1016/j.bbi.2005.10.115
#109 Relationship between physiological stress indices and salivary cortisol level Seikwon Park a, Dongsoo Kim b a
Department of Industrial Engineering, Korean Air Force Academy, Republic of Korea b Department of Chemistry, Korean Air Force Academy, Republic of Korea The physiological and biochemical responses of healthy men and women who are cadets of the Korea Air Force Academy were measured under the normal situation (n = 27). We reported that salivary cortisol levels of individual having over 8.5 ng/ml were significantly correlated with self-reported psychological stress test score. We have investigated physiological stress indices to measure realtime life stress level. Heart rate variability (HRV), skin temperature, blood pressure (BP), heart rate (HR), and galvanic skin response (GSR) were selected as physiological stress indices. All physiological data were obtained simultaneously by the BioPac, and saliva samples were collected around 7 am on same day. The difference of skin temperature between forehead and fingertip correlated significantly
Abstracts / Brain, Behavior, and Immunity 19 (2005) e43–e74
with salivary cortisol level (p < .01). The LF (low frequency)/HF (high frequency) ratio of HRV correlated significantly with salivary cortisol level (p < .05). However, BP, HR, and GSR correlated relatively with salivary cortisol level. We suggest that LF/HF ratio of HRV and the difference of skin temperature between main body and the end of limbs may be good indices of chronic and relatively low level of life stress, and may apply to measure real time stress level of individual. doi:10.1016/j.bbi.2005.10.116
#110 Anxiety-like behavior following cecal infection with Campylobacter jejuni in mice: Potential brain substrates Su-Mi Park a, Ron P.A. Gaykema a, Noel Opitz b, Mark Lyte b, Lisa E. Goehler a
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the only brain region in which ANOVA showed a significant interaction between C. jejuni treatment and the behavioral test was the BST. In addition, multiple regression showed significant correlations among the activity of NTS, PVN, and BLA. Furthermore, the regression test showed that the mice with increased activity of BLA were less likely to enter or travel to the center area of the hole board, indicating the contribution of the BLA activity to the induction of anxiety-like behavior. These findings suggest that the BLA, which reportedly contributes to conditioned fear responses, may also play a role in infection-enhanced anxiety-like response to naturally aversive situation, e.g., open spaces, perhaps in concert with the NTS and PVN responses to C. jejuni infection. Supported by NIH Grants MH 50431, MH 64648, MH 68834, and Institutional funds from the University of Virginia. doi:10.1016/j.bbi.2005.10.117
a
Program in Sensory and Systems Neuroscience, Department of Psychology, University of Virginia, Charlottesville, VA 22904, USA b Department of Surgery, Minneapolis Medical Research Foundation/Hennepin County Medical Center, Minneapolis, MN 55404, USA Infection with the gut bacterium Campylobacter jejuni (C. jejuni) produces anxiety-like behavior in mice and c-Fos expression (an activation marker in neurons) in brain regions that process autonomic information. As yet unresolved are the specific neural substrates that mediate the infection-induced anxiety-like behavior. Male mice were inoculated per orally with either approximately 5 · 107 to 108 of C. jejuni or sterile saline, and allowed to survive for 6–7 h. They were then allowed to explore an open field/hole board for 5 min. Another group of mice were inoculated but kept in their home cage. One hour after testing (to allow for behaviorally relevant c-Fos induction) the mice were deeply anesthetized, and perfused with saline followed by 4% paraformaldehyde. The brains were removed, sectioned on a vibratome, and processed for immunohistochemical localization of the c-Fos protein. Data were analyzed using analysis of variance (ANOVA) and multiple regression. Infection with C. jejuni resulted in anxiety-like behavior as evinced by fewer entries into the very center zone and shorter distance traveled in the center area of the hole board by the infected mice. The infected mice did not show any apparent sickness behaviors and their total distance traveled on the hole board was not different from the control group. Campylobacter jejuni induced c-Fos expression in the nucleus solitary tract (NTS), lateral parabrachial nucleus, locus coeruleus, paraventricular nucleus (PVN), bed nucleus of stria terminalis (BST) and central and basolateral nuclei of the amygdala (CEA & BLA) compared to the controls, whereas neural activity in the PVN, BLA, and the lateral septal area was associated with the testing condition (as compared to home-cage controls). Interestingly,
#111 Intraperitoneal lipopolysaccharide produces changes in brain metabolic activity as measured by [18F]FDG in the rat Gregory H. Pelton a,b, Leon N. Lyazidi a, Raymond C. Chang b, Davangere P. Devanand a,b, Harold A. Sackheim a,b, Rikki N. Waterhouse a,b a
Columbia University, College of Physicians and Surgeons, USA b Department of Psychiatry, New York State Psychiatric Institute, USA Background: In animals and humans, systematically administered lipopolysaccharide (LPS) produces a classic cascade of physiological and behavioral symptoms termed ‘‘sickness behavior.’’ These behaviors and associated brain neurochemical and metabolic changes are not well defined yet might be important in specific psychiatric or neurological illnesses. We tested the hypothesis that peripheral LPS challenge would induce changes in neuronal metabolism. Methods: In study 1, we determined the time at which maximum activity was achieved in cortical regions of interest. LPS (intraperitoneal (IP), 100 lg/kg in 400 ll saline) or saline (IP, 400 ll) were administered to conscious adult male rats (260–320 g). One hour, 2 h, or 6 h after LPS [18F]FDG, a marker of glucose metabolism (IV, 25 lCi, 100 ll saline) was administered via tail vein. Animals were sacrificed 45 min post-FDG injection and the concentration (%ID/g) of [18F]FDG in blood and select brain regions was determined by biodistribution analysis. In study 2, we sought to determine the optimal dose of LPS required for activation in cortical regions of interest. LPS (IP, 5, 50, or 100 lg/kg in 400 ll saline) or saline (IP, 400 ll) were administered to conscious adult male rats (260–320 g), followed 2 h later by [18F]FDG, via tail vein. Animals were sacrificed 45 min post-FDG injection and the concentration (%ID/g) of [18F]FDG in blood and select brain regions was determined by biodistribution analysis.
Abstracts / Brain, Behavior, and Immunity 19 (2005) e43–e74
#107 Indicators of innate immune system activity in humans increase with psychosocial stressor challenge: Major depressives vs. non-depressives Thaddeus W.W. Pace, Tanja M. Mletzko, Oyetunde Alagbe, Gerald J. Vogt, Fang Hu, Andrew H. Miller, Erica C. Bruce, Dominique L. Musselman, Charles B. Nemeroff, Christine M. Heim Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA Prior studies have demonstrated that acute stressor challenge increases plasma levels of proinflammatory cytokines such interleukin-6 (IL-6), and the number of natural killer (NK) cells in bulk peripheral blood mononuclear cells (PBMCs). In addition, acute stressor challenge has also been found to increase DNA binding activity of nuclear factor-jB (NF-jB) in bulk PBMCs. NF-jB is of interest because it is an important regulator of genes associated with immune system function. We report here changes in PBMC NF-jB DNA binding, plasma IL-6, and NK cell proportions in PBMCs as a result of challenge with the Trier Social Stressor Test (TSST) in clinically depressed (MDDs; n = 12) and non-depressed (NDs, n = 19) male participants (mean age 31). Plasma IL-6 was measured with an enzyme-linked immunosorbent assay (ELISA) (R&D Systems), NK cell numbers were determined via flow cytometry, and NF-jB DNA binding was measured with an ELISA-based kit built upon the consensus DNA sequence for NF-jB (Active Motif). On the whole, TSST challenge increased all three measures of innate immune function relative to baseline values. Although in this study MDDs did not have higher basal levels of plasma IL-6, NK cell numbers, or NF-jB binding relative to NDs, they did exhibit a greater increase in NF-jB binding and plasma IL-6 as a result of TSST challenge. Maximum plasma IL-6 was also significantly correlated with maximum NF-jB DNA binding. However, NK cell numbers did not differ between the groups during or after the stressor. These data suggest that major depressives may have an enhanced innate immune response to a psychosocial stressor measurable at the level of NF-jB. Such a increased response could be due to the lack of inhibitory effects normally exerted over innate immunity, such as those from endogenous glucocorticoids. Supported by NARSAD Young Investigator Award to CHM; MH058922-06 to CBN & AHM. doi:10.1016/j.bbi.2005.10.114
#108 The androgen, androstenediol, counter-regulates glucocorticoid-mediated suppression of inflammatory gene expression and accelerates wound repair David A. Padgett, Michael J. Farrow, Cynthia C. Head, John F. Sheridan The Institute for Behavioral Medicine Research, The Ohio State University, USA
Glucocorticoids (GC), which are elevated by stress, suppress cytokine responses during the inflammatory stage of wound healing. Suppression of inflammatory gene expression is associated with delayed closure of cutaneous wounds. Treatment of mice with the androgen, androstenediol (AED), restored cytokine responses in stressed animals and also accelerated wound closure. To determine a mechanism of action, these current experiments were designed to distinguish differences between AED and GC in regulating inflammatory gene expression. We hypothesized that AED would act as an agonist of the androgen receptor (AR), counter the anti-inflammatory influence of GC, and modulate NF-jB activity. To test this, RAW 264.7 macrophages were stimulated with LPS to induce inflammatory cytokine production. Changes in inflammatory gene transcription after treatment with dexamethasone (DEX) and/or AED were assessed using focused microarrays, real-time PCR and ELISA. A transcription factor binding assay was employed to determine differences in activation of NF-jB. The results demonstrated that AED counter-regulated DEX-induced suppression of multiple genes involved in inflammation including TLR-4 and TNF-a. AED also enhanced the quantity of transcriptionally active p65 which was suppressed by DEX treatment alone. The anti-glucocorticoid effects of AED were blocked by cyproterone acetate (an AR antagonist). These observations indicate that AED modulates the anti-inflammatory transcriptional influence of GC in an androgen receptor-dependent manner. Supported by MH56899 to DAP, T32DE014320 to MJF, and F30DE14304 to CCH. doi:10.1016/j.bbi.2005.10.115
#109 Relationship between physiological stress indices and salivary cortisol level Seikwon Park a, Dongsoo Kim b a
Department of Industrial Engineering, Korean Air Force Academy, Republic of Korea b Department of Chemistry, Korean Air Force Academy, Republic of Korea The physiological and biochemical responses of healthy men and women who are cadets of the Korea Air Force Academy were measured under the normal situation (n = 27). We reported that salivary cortisol levels of individual having over 8.5 ng/ml were significantly correlated with self-reported psychological stress test score. We have investigated physiological stress indices to measure realtime life stress level. Heart rate variability (HRV), skin temperature, blood pressure (BP), heart rate (HR), and galvanic skin response (GSR) were selected as physiological stress indices. All physiological data were obtained simultaneously by the BioPac, and saliva samples were collected around 7 am on same day. The difference of skin temperature between forehead and fingertip correlated significantly
Abstracts / Brain, Behavior, and Immunity 19 (2005) e43–e74
with salivary cortisol level (p < .01). The LF (low frequency)/HF (high frequency) ratio of HRV correlated significantly with salivary cortisol level (p < .05). However, BP, HR, and GSR correlated relatively with salivary cortisol level. We suggest that LF/HF ratio of HRV and the difference of skin temperature between main body and the end of limbs may be good indices of chronic and relatively low level of life stress, and may apply to measure real time stress level of individual. doi:10.1016/j.bbi.2005.10.116
#110 Anxiety-like behavior following cecal infection with Campylobacter jejuni in mice: Potential brain substrates Su-Mi Park a, Ron P.A. Gaykema a, Noel Opitz b, Mark Lyte b, Lisa E. Goehler a
e57
the only brain region in which ANOVA showed a significant interaction between C. jejuni treatment and the behavioral test was the BST. In addition, multiple regression showed significant correlations among the activity of NTS, PVN, and BLA. Furthermore, the regression test showed that the mice with increased activity of BLA were less likely to enter or travel to the center area of the hole board, indicating the contribution of the BLA activity to the induction of anxiety-like behavior. These findings suggest that the BLA, which reportedly contributes to conditioned fear responses, may also play a role in infection-enhanced anxiety-like response to naturally aversive situation, e.g., open spaces, perhaps in concert with the NTS and PVN responses to C. jejuni infection. Supported by NIH Grants MH 50431, MH 64648, MH 68834, and Institutional funds from the University of Virginia. doi:10.1016/j.bbi.2005.10.117
a
Program in Sensory and Systems Neuroscience, Department of Psychology, University of Virginia, Charlottesville, VA 22904, USA b Department of Surgery, Minneapolis Medical Research Foundation/Hennepin County Medical Center, Minneapolis, MN 55404, USA Infection with the gut bacterium Campylobacter jejuni (C. jejuni) produces anxiety-like behavior in mice and c-Fos expression (an activation marker in neurons) in brain regions that process autonomic information. As yet unresolved are the specific neural substrates that mediate the infection-induced anxiety-like behavior. Male mice were inoculated per orally with either approximately 5 · 107 to 108 of C. jejuni or sterile saline, and allowed to survive for 6–7 h. They were then allowed to explore an open field/hole board for 5 min. Another group of mice were inoculated but kept in their home cage. One hour after testing (to allow for behaviorally relevant c-Fos induction) the mice were deeply anesthetized, and perfused with saline followed by 4% paraformaldehyde. The brains were removed, sectioned on a vibratome, and processed for immunohistochemical localization of the c-Fos protein. Data were analyzed using analysis of variance (ANOVA) and multiple regression. Infection with C. jejuni resulted in anxiety-like behavior as evinced by fewer entries into the very center zone and shorter distance traveled in the center area of the hole board by the infected mice. The infected mice did not show any apparent sickness behaviors and their total distance traveled on the hole board was not different from the control group. Campylobacter jejuni induced c-Fos expression in the nucleus solitary tract (NTS), lateral parabrachial nucleus, locus coeruleus, paraventricular nucleus (PVN), bed nucleus of stria terminalis (BST) and central and basolateral nuclei of the amygdala (CEA & BLA) compared to the controls, whereas neural activity in the PVN, BLA, and the lateral septal area was associated with the testing condition (as compared to home-cage controls). Interestingly,
#111 Intraperitoneal lipopolysaccharide produces changes in brain metabolic activity as measured by [18F]FDG in the rat Gregory H. Pelton a,b, Leon N. Lyazidi a, Raymond C. Chang b, Davangere P. Devanand a,b, Harold A. Sackheim a,b, Rikki N. Waterhouse a,b a
Columbia University, College of Physicians and Surgeons, USA b Department of Psychiatry, New York State Psychiatric Institute, USA Background: In animals and humans, systematically administered lipopolysaccharide (LPS) produces a classic cascade of physiological and behavioral symptoms termed ‘‘sickness behavior.’’ These behaviors and associated brain neurochemical and metabolic changes are not well defined yet might be important in specific psychiatric or neurological illnesses. We tested the hypothesis that peripheral LPS challenge would induce changes in neuronal metabolism. Methods: In study 1, we determined the time at which maximum activity was achieved in cortical regions of interest. LPS (intraperitoneal (IP), 100 lg/kg in 400 ll saline) or saline (IP, 400 ll) were administered to conscious adult male rats (260–320 g). One hour, 2 h, or 6 h after LPS [18F]FDG, a marker of glucose metabolism (IV, 25 lCi, 100 ll saline) was administered via tail vein. Animals were sacrificed 45 min post-FDG injection and the concentration (%ID/g) of [18F]FDG in blood and select brain regions was determined by biodistribution analysis. In study 2, we sought to determine the optimal dose of LPS required for activation in cortical regions of interest. LPS (IP, 5, 50, or 100 lg/kg in 400 ll saline) or saline (IP, 400 ll) were administered to conscious adult male rats (260–320 g), followed 2 h later by [18F]FDG, via tail vein. Animals were sacrificed 45 min post-FDG injection and the concentration (%ID/g) of [18F]FDG in blood and select brain regions was determined by biodistribution analysis.