- Email: [email protected]
150. Somatic pain sensitivity during experimentally-induced inflammation in humans
Abstracts / Brain, Behavior, and Immunity 32 (2013) e1–e47
vs. non-CG). These molecular insights might help to understand the health effects of bereavement. http://dx.doi.org/10.1016/j.bbi.2013.07.158
147. Effects of maternal immune activation on embryonic hypothalamic development C.M. Marsters a,b,c, D.M. Kurrasch c, Q.J. Pittman b
e43
were reduced during the hospital stay and at follow-up. The bipolar depressed group also had elevated levels of antibodies to the nucleocapsid protein of the SARS strain of coronavirus, while elevated levels of these antibodies were not found in the other groups. Our study indicates that bipolar disorder depression is associated with immune activation, particularly during acute exacerbations. These findings may lead to the development of new methods of prevention and treatment. http://dx.doi.org/10.1016/j.bbi.2013.07.160
a
University of Calgary, Foothills Hospital Campus, Lab #2146, 3330 Hospital Dr. N.W. HSC, Calgary, Alberta, USA b Hotchkiss Brain Institute, USA c Alberta Children’s Hospital Research Institute, USA Maternal infection has been linked to disorders such as autism, anxiety, cerebral palsy, and schizophrenia in the offspring children. Recent research suggests that an inflammatory immune response mounted by the mother may alter the fetal environment and disrupt normal developmental processes. It has been previously shown that increased inflammatory cytokine levels in fetal brains, as seen during maternal inflammation, can affect the timing of neuronal differentiation and survival, thereby providing a potential link between maternal inflammation, fetal neurodevelopment, and the onset of disorders during childhood. Here we seek to explore whether maternal inflammation causes changes in hypothalamic development, a key region known to contribute to various disorders. Our overarching goal is to determine whether exposure to maternal inflammation at specific periods in gestation leads to changes in the onset and/or duration of hypothalamic neurogenesis, as an entry point towards linking in utero environment with adverse health outcome in offspring. Here we examine the timing of hypothalamic neuronal birth using 5-Bromol-20 -deoxyuridine (BrdU) labeling to determine whether neurogenesis or gliogenesis is affected in embryos by onset of maternal inflammation induced by lipopolysaccharide (LPS) during key windows of development. Recently, we have looked for alternations in neuronal birth following onset of embryonic hypothalamic neurogenesis in pups born of dams treated with LPS. This exposed whether hypothalamic development in fetal brains was perturbed after induction of maternal inflammation. http://dx.doi.org/10.1016/j.bbi.2013.07.159
148. Acute bipolar disorder depression is associated with immune activation F. Dickerson a,b, R. Yolken b a
Sheppard Pratt, 6501 North Charles St., Baltimore, MD 21204, USA b Johns Hopkins School of Medicine, USA Recent studies indicate that immune activation may be an important component of the pathogenesis of bipolar disorder. The study sample consists of 40 patients admitted to the hospital with a diagnosis of acute bipolar depression. Blood samples were drawn at 3 time points: at time of hospital admission, during the acute hospital stay, and at a six month follow-up. Inflammatory markers were measured including C-reactive protein (CRP), Pentraxin 3 (PTX3), and antibodies to infectious agents. The markers in the bipolar depressed patients were studied over the 3 time points and also compared to those in other groups: 60 hospitalized for acute mania; 69 with recent onset psychosis; 246 with multi-episode schizophrenia; 98 with bipolar disorder not selected for mania or depression; and 222 non-psychiatric controls. The bipolar depressed patients had elevated levels of CRP at all 3 time points. The bipolar depressed patients also had elevated levels of PTX3 at hospital admission which
149. Epigenetic Alterations and an Increased Frequency of Micronuclei in Women With Fibromyalgia D. Lyon, V. Menzies, K. Archer, J.R. Brumelle, K.H. Jones, G. Gao, R.K. Elswick Jr., T. York, C. Jackson-Cook Virginia Commonwealth University, School of Nursing, 1220 E. Broad Street, Box 980567, Richmond, VA 23298, USA Fibromyalgia (FM), is characterized by chronic widespread pain, fatigue and cognitive/mood disturbances, and leads to reduced workplace productivity and increased health care/disability expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM (N = 10) to those seen in comparably aged healthy controls (N = 42 [MN]; N = 8 [methylation]). The mean MN frequency of women with FM (51.4 + 21.9) was significantly higher than that of the controls (15.8 ± 8.5) (v2 =45.552; df = 1; p = 1.49 1011). Significant differences (N = 69 sites) in methylation patterns were also observed between cohorts. The majority of the differentially methylated (DM) sites (91%) were attributable to increased values in the women having FM. The DM included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included (but are not limited to) BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1. These results support the need for future research to further examine the potential biological pathway of epigenetic and acquired chromosomal alterations as a correlate, or possible biological mechanism, leading to/ resulting from FM. http://dx.doi.org/10.1016/j.bbi.2013.07.161
150. Somatic pain sensitivity during experimentally-induced inflammation in humans A. Wegner a,b, S. Elsenbruch a, J. Maluck a, M. Schedlowski a, S. Benson a a
Inst. of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany, Hufelandstrasse 55, Essen 45147, USA b Clinic for Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Germany Background: Enhanced pain sensitivity is a component of sickness behavior in experimental animals. However, data on the effects of systemic immune activation on pain processing in humans are rare thus far. Therefore, the goal of this ongoing study is to analyze timeand dose-dependent effects of experimentally-induced systemic immune activation on somatic pain responses in healthy male volunteers. Methods: Employing a randomized, placebo-controlled between-group design, healthy male subjects receive an i.v. injection
e44
Abstracts / Brain, Behavior, and Immunity 32 (2013) e1–e47
of either lipopolysaccharide (LPS groups; 0.4 ng/kg or 0.8 ng/kg) or saline (control group). Pain thresholds are analyzed by using pressure algometry, pinprick stimulation and ice water test and are evaluated with visual analogue scales before (baseline) and 1, 3 and 6 h post-injection. Blood samples are taken at baseline, and 1, 2, 3, 4, and 6 h after injection to assess plasma levels of proinflammatory cytokines. Results: LPS injection resulted in a systemic, transient inflammatory response, reflected by significant increases in TNF-alpha, interleukin-6 plasma levels, and body temperature (all p < .001). LPS-treated subjects rated the somatic pain stimuli significantly more painful compared to controls (p < .05), whereas no significant differences between the LPS and control conditions are observed for pinprick stimulation and ice water test. Conclusions: These preliminary results support an impact of systemic inflammation on human somatic pain sensitivity, which may have implications for the pathophysiology of chronic pain or hyperalgesia. http://dx.doi.org/10.1016/j.bbi.2013.07.162
151. Neuroinflammation: An animal model of fatigue induced through interleukin-1 beta D. Bonsall, P.C. Molyneux, M.E. Harrington Smith College, Psychology, 44 College Lane, Clarke Science Center SR434, Northampton, MA 01063, USA The immune system, in response to insult or challenge, is able to induce a range of behavioral modifications, collectively known as sickness behavior. These include fatigue, fever, social withdrawal and reduced food intake. Here we describe a recently developed mouse-model of acute fatigue, utilizing the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta). Six month old female C57Bl/6 J mice peripherally administered with 400 ng IL-1 beta show a significant reduction in voluntary wheel running behavior (p < 0.01) over 24 h. Notably, general locomotor activity, as determined through external motion sensors and abdominally-inserted telemetry probes, shows no significant changes with IL-1 beta administration (p > 0.05) over this same period. Other symptoms associated with sickness behavior, including fever and weight loss also remain unaffected by IL-1 beta administration (p > 0.05). Furthermore, we demonstrate dose-dependent effects and age- and sex-related differences in behavioral responses to IL-1 beta treatment. Preliminary data from mice administered with IL-1 beta in the lateral ventricle suggest a centrally mediated fatigue response. We explore these central effects using immunohistochemistry to study changes in central immune responses, specifically microglial activation, in several regions throughout the brain related to the pathways of arousal and motivational responses. This work was supported by the NIH grant R21NR012845. http://dx.doi.org/10.1016/j.bbi.2013.07.163
152. Cortisol reacitivity and body mass index in pre-adolescent children M.J. Slattery, N.A. Miller, A.J. Grieve University of Wisconsin School of Medicine and Public Heatlh, Psychiatry, 6001 Research Park Boulevard, Madison, WI 53719, USA Background: Considerable research has focused on alterations in the hypothalamic–pituitary–adrenal (HPA) stress response and obesity in adults, with most studies reporting an association of increased body mass index (BMI) with increased HPA activity. Early detection of HPA alterations in younger children with increased BMI
is critical for targeted intervention and prevention of later adverse health outcomes. This study examines the association of body mass index (BMI) with HPA reactivity to an acute stressor in pre-adolescent children, and further, whether the relationship is influenced by the presence of anxiety or depression. METHODS: A social evaluative Cold Pressor Task was used to elicit an acute stress response among children aged 8–12 years (n = 43). Repeated saliva samples were assayed for cortisol to determine area under the curve with respect to increase (AUCi) and ground (AUCg). Anxiety and depressive symptoms were assessed with standardized measures. Bivariate correlational analyses examined relationships of BMI with AUCi/ AUCg; linear regression assessed a combined model of BMI and anxiety/depressive symptoms predicting AUCi/AUCg. RESULTS: BMI was inversely associated with AUCg (r = .47, p = .002) but not with AUCi (r = .04, p = .79); this relationship remained significant in the multiple regression model. Conclusions: The relationship between BMI and HPA reactivity may differ in children vs. adults. Results additionally underscore the need to assess both cortisol output (AUCg) and HPA reactivity (AUCi) in these investigations. http://dx.doi.org/10.1016/j.bbi.2013.07.164
153. Stress, allergy and the skin: altered cytokine profile may be linked to the non-neuronal cholinergic system (NNCS) F.R. Rommel a, A. Michenko b, J. Kupfer c, S. Tumala a, B. Raghavan a, U. Gieler d, E.M. Peters a,b a Psychoneuroimmunology Laboratory, Department of Psychosomatics and Psychotherapy, Justus-Liebig-University, Giessen 35392, Germany b Charité Center 12 Internal Medicine and Dermatology, Psycho-NeuroImmunology Skin Research Group, Universitätsmedizin Berlin, Berlin, Germany c Institute of Medical Psychology, Justus-Liebig University, Giessen, Germany d Department of Dermatology, University Hospital Giessen, Giessen, Germany
The cholinergic system enables adaptation to environmental and endogenous stressors via neuroimmune responses. Self-environment borders such as skin are in great need of effective adaptation. We here compared skin if mice exposed to noise stress with unstressed and mice and humans with allergic/atopic dermatitis (AlD/AD) exposed to noise or Trier Social Stress Test (TSST). Microarray analysis revealed specific regulation of cytokines depending on muscarinergic and nicotinergic acetylcholine receptor (m- and n-AChR) activation. Downregulation of TNFa receptor 1 (TNFR1) and upregulation of TNFR5 in stressed mouse skin hints at downregulation of TH1 and upregulation of TH2 immune responses. Immunohistomorphometry revealed that mast cells in AlD downregulate the acetylcholine synthesizing enzyme ChAT while upregulating a7nAChR and TNFa, which was reversed after AlD-worsening additional noise stress. In AD patients SP-cleaving tryptase + mast cells were lowest in lesional skin while epidermal thickness was highest. TSST increased mast cell numbers in healthy and decreased them in lesional skin, while epidermal thickness was increased in nonlesional skin. qRT-PCR showed lowest a7nAchR levels in AD skin and after TSST slightly increased levels solely in lesional AD skin. SLURP1 (endogenous a7nAchR ligand) was lowest in non-lesional AD skin and TSST decreased it in healthy skin. We conclude that stress affects cutaneous NNCS both in mice and humans facilitating AlD/AD. Further studies are needed to elucidate the underlying molecular mechanisms and functional relevance. http://dx.doi.org/10.1016/j.bbi.2013.07.165
vs. non-CG). These molecular insights might help to understand the health effects of bereavement. http://dx.doi.org/10.1016/j.bbi.2013.07.158
147. Effects of maternal immune activation on embryonic hypothalamic development C.M. Marsters a,b,c, D.M. Kurrasch c, Q.J. Pittman b
e43
were reduced during the hospital stay and at follow-up. The bipolar depressed group also had elevated levels of antibodies to the nucleocapsid protein of the SARS strain of coronavirus, while elevated levels of these antibodies were not found in the other groups. Our study indicates that bipolar disorder depression is associated with immune activation, particularly during acute exacerbations. These findings may lead to the development of new methods of prevention and treatment. http://dx.doi.org/10.1016/j.bbi.2013.07.160
a
University of Calgary, Foothills Hospital Campus, Lab #2146, 3330 Hospital Dr. N.W. HSC, Calgary, Alberta, USA b Hotchkiss Brain Institute, USA c Alberta Children’s Hospital Research Institute, USA Maternal infection has been linked to disorders such as autism, anxiety, cerebral palsy, and schizophrenia in the offspring children. Recent research suggests that an inflammatory immune response mounted by the mother may alter the fetal environment and disrupt normal developmental processes. It has been previously shown that increased inflammatory cytokine levels in fetal brains, as seen during maternal inflammation, can affect the timing of neuronal differentiation and survival, thereby providing a potential link between maternal inflammation, fetal neurodevelopment, and the onset of disorders during childhood. Here we seek to explore whether maternal inflammation causes changes in hypothalamic development, a key region known to contribute to various disorders. Our overarching goal is to determine whether exposure to maternal inflammation at specific periods in gestation leads to changes in the onset and/or duration of hypothalamic neurogenesis, as an entry point towards linking in utero environment with adverse health outcome in offspring. Here we examine the timing of hypothalamic neuronal birth using 5-Bromol-20 -deoxyuridine (BrdU) labeling to determine whether neurogenesis or gliogenesis is affected in embryos by onset of maternal inflammation induced by lipopolysaccharide (LPS) during key windows of development. Recently, we have looked for alternations in neuronal birth following onset of embryonic hypothalamic neurogenesis in pups born of dams treated with LPS. This exposed whether hypothalamic development in fetal brains was perturbed after induction of maternal inflammation. http://dx.doi.org/10.1016/j.bbi.2013.07.159
148. Acute bipolar disorder depression is associated with immune activation F. Dickerson a,b, R. Yolken b a
Sheppard Pratt, 6501 North Charles St., Baltimore, MD 21204, USA b Johns Hopkins School of Medicine, USA Recent studies indicate that immune activation may be an important component of the pathogenesis of bipolar disorder. The study sample consists of 40 patients admitted to the hospital with a diagnosis of acute bipolar depression. Blood samples were drawn at 3 time points: at time of hospital admission, during the acute hospital stay, and at a six month follow-up. Inflammatory markers were measured including C-reactive protein (CRP), Pentraxin 3 (PTX3), and antibodies to infectious agents. The markers in the bipolar depressed patients were studied over the 3 time points and also compared to those in other groups: 60 hospitalized for acute mania; 69 with recent onset psychosis; 246 with multi-episode schizophrenia; 98 with bipolar disorder not selected for mania or depression; and 222 non-psychiatric controls. The bipolar depressed patients had elevated levels of CRP at all 3 time points. The bipolar depressed patients also had elevated levels of PTX3 at hospital admission which
149. Epigenetic Alterations and an Increased Frequency of Micronuclei in Women With Fibromyalgia D. Lyon, V. Menzies, K. Archer, J.R. Brumelle, K.H. Jones, G. Gao, R.K. Elswick Jr., T. York, C. Jackson-Cook Virginia Commonwealth University, School of Nursing, 1220 E. Broad Street, Box 980567, Richmond, VA 23298, USA Fibromyalgia (FM), is characterized by chronic widespread pain, fatigue and cognitive/mood disturbances, and leads to reduced workplace productivity and increased health care/disability expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM (N = 10) to those seen in comparably aged healthy controls (N = 42 [MN]; N = 8 [methylation]). The mean MN frequency of women with FM (51.4 + 21.9) was significantly higher than that of the controls (15.8 ± 8.5) (v2 =45.552; df = 1; p = 1.49 1011). Significant differences (N = 69 sites) in methylation patterns were also observed between cohorts. The majority of the differentially methylated (DM) sites (91%) were attributable to increased values in the women having FM. The DM included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included (but are not limited to) BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1. These results support the need for future research to further examine the potential biological pathway of epigenetic and acquired chromosomal alterations as a correlate, or possible biological mechanism, leading to/ resulting from FM. http://dx.doi.org/10.1016/j.bbi.2013.07.161
150. Somatic pain sensitivity during experimentally-induced inflammation in humans A. Wegner a,b, S. Elsenbruch a, J. Maluck a, M. Schedlowski a, S. Benson a a
Inst. of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany, Hufelandstrasse 55, Essen 45147, USA b Clinic for Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Germany Background: Enhanced pain sensitivity is a component of sickness behavior in experimental animals. However, data on the effects of systemic immune activation on pain processing in humans are rare thus far. Therefore, the goal of this ongoing study is to analyze timeand dose-dependent effects of experimentally-induced systemic immune activation on somatic pain responses in healthy male volunteers. Methods: Employing a randomized, placebo-controlled between-group design, healthy male subjects receive an i.v. injection
e44
Abstracts / Brain, Behavior, and Immunity 32 (2013) e1–e47
of either lipopolysaccharide (LPS groups; 0.4 ng/kg or 0.8 ng/kg) or saline (control group). Pain thresholds are analyzed by using pressure algometry, pinprick stimulation and ice water test and are evaluated with visual analogue scales before (baseline) and 1, 3 and 6 h post-injection. Blood samples are taken at baseline, and 1, 2, 3, 4, and 6 h after injection to assess plasma levels of proinflammatory cytokines. Results: LPS injection resulted in a systemic, transient inflammatory response, reflected by significant increases in TNF-alpha, interleukin-6 plasma levels, and body temperature (all p < .001). LPS-treated subjects rated the somatic pain stimuli significantly more painful compared to controls (p < .05), whereas no significant differences between the LPS and control conditions are observed for pinprick stimulation and ice water test. Conclusions: These preliminary results support an impact of systemic inflammation on human somatic pain sensitivity, which may have implications for the pathophysiology of chronic pain or hyperalgesia. http://dx.doi.org/10.1016/j.bbi.2013.07.162
151. Neuroinflammation: An animal model of fatigue induced through interleukin-1 beta D. Bonsall, P.C. Molyneux, M.E. Harrington Smith College, Psychology, 44 College Lane, Clarke Science Center SR434, Northampton, MA 01063, USA The immune system, in response to insult or challenge, is able to induce a range of behavioral modifications, collectively known as sickness behavior. These include fatigue, fever, social withdrawal and reduced food intake. Here we describe a recently developed mouse-model of acute fatigue, utilizing the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta). Six month old female C57Bl/6 J mice peripherally administered with 400 ng IL-1 beta show a significant reduction in voluntary wheel running behavior (p < 0.01) over 24 h. Notably, general locomotor activity, as determined through external motion sensors and abdominally-inserted telemetry probes, shows no significant changes with IL-1 beta administration (p > 0.05) over this same period. Other symptoms associated with sickness behavior, including fever and weight loss also remain unaffected by IL-1 beta administration (p > 0.05). Furthermore, we demonstrate dose-dependent effects and age- and sex-related differences in behavioral responses to IL-1 beta treatment. Preliminary data from mice administered with IL-1 beta in the lateral ventricle suggest a centrally mediated fatigue response. We explore these central effects using immunohistochemistry to study changes in central immune responses, specifically microglial activation, in several regions throughout the brain related to the pathways of arousal and motivational responses. This work was supported by the NIH grant R21NR012845. http://dx.doi.org/10.1016/j.bbi.2013.07.163
152. Cortisol reacitivity and body mass index in pre-adolescent children M.J. Slattery, N.A. Miller, A.J. Grieve University of Wisconsin School of Medicine and Public Heatlh, Psychiatry, 6001 Research Park Boulevard, Madison, WI 53719, USA Background: Considerable research has focused on alterations in the hypothalamic–pituitary–adrenal (HPA) stress response and obesity in adults, with most studies reporting an association of increased body mass index (BMI) with increased HPA activity. Early detection of HPA alterations in younger children with increased BMI
is critical for targeted intervention and prevention of later adverse health outcomes. This study examines the association of body mass index (BMI) with HPA reactivity to an acute stressor in pre-adolescent children, and further, whether the relationship is influenced by the presence of anxiety or depression. METHODS: A social evaluative Cold Pressor Task was used to elicit an acute stress response among children aged 8–12 years (n = 43). Repeated saliva samples were assayed for cortisol to determine area under the curve with respect to increase (AUCi) and ground (AUCg). Anxiety and depressive symptoms were assessed with standardized measures. Bivariate correlational analyses examined relationships of BMI with AUCi/ AUCg; linear regression assessed a combined model of BMI and anxiety/depressive symptoms predicting AUCi/AUCg. RESULTS: BMI was inversely associated with AUCg (r = .47, p = .002) but not with AUCi (r = .04, p = .79); this relationship remained significant in the multiple regression model. Conclusions: The relationship between BMI and HPA reactivity may differ in children vs. adults. Results additionally underscore the need to assess both cortisol output (AUCg) and HPA reactivity (AUCi) in these investigations. http://dx.doi.org/10.1016/j.bbi.2013.07.164
153. Stress, allergy and the skin: altered cytokine profile may be linked to the non-neuronal cholinergic system (NNCS) F.R. Rommel a, A. Michenko b, J. Kupfer c, S. Tumala a, B. Raghavan a, U. Gieler d, E.M. Peters a,b a Psychoneuroimmunology Laboratory, Department of Psychosomatics and Psychotherapy, Justus-Liebig-University, Giessen 35392, Germany b Charité Center 12 Internal Medicine and Dermatology, Psycho-NeuroImmunology Skin Research Group, Universitätsmedizin Berlin, Berlin, Germany c Institute of Medical Psychology, Justus-Liebig University, Giessen, Germany d Department of Dermatology, University Hospital Giessen, Giessen, Germany
The cholinergic system enables adaptation to environmental and endogenous stressors via neuroimmune responses. Self-environment borders such as skin are in great need of effective adaptation. We here compared skin if mice exposed to noise stress with unstressed and mice and humans with allergic/atopic dermatitis (AlD/AD) exposed to noise or Trier Social Stress Test (TSST). Microarray analysis revealed specific regulation of cytokines depending on muscarinergic and nicotinergic acetylcholine receptor (m- and n-AChR) activation. Downregulation of TNFa receptor 1 (TNFR1) and upregulation of TNFR5 in stressed mouse skin hints at downregulation of TH1 and upregulation of TH2 immune responses. Immunohistomorphometry revealed that mast cells in AlD downregulate the acetylcholine synthesizing enzyme ChAT while upregulating a7nAChR and TNFa, which was reversed after AlD-worsening additional noise stress. In AD patients SP-cleaving tryptase + mast cells were lowest in lesional skin while epidermal thickness was highest. TSST increased mast cell numbers in healthy and decreased them in lesional skin, while epidermal thickness was increased in nonlesional skin. qRT-PCR showed lowest a7nAchR levels in AD skin and after TSST slightly increased levels solely in lesional AD skin. SLURP1 (endogenous a7nAchR ligand) was lowest in non-lesional AD skin and TSST decreased it in healthy skin. We conclude that stress affects cutaneous NNCS both in mice and humans facilitating AlD/AD. Further studies are needed to elucidate the underlying molecular mechanisms and functional relevance. http://dx.doi.org/10.1016/j.bbi.2013.07.165