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212. Dendritic cells in the brain: Distribution and function
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PNIRS meeting abstracts / Brain, Behavior, and Immunity 25 (2011) S179–S242
depressed patients, approximately one third are treatment resistant. Although the neurobiology of treatment resistant depression (TRD) is poorly understood, a number of factors have been associated with antidepressant non-response including obesity, early life stress, personality disorders, bipolar depression and medical co-morbidity. One pathophysiologic mechanism that may link these factors with TRD is inflammation. In addition to a direct relationship between inflammatory markers and TRD, increased inflammation is associated with depression in obesity, early life stress, and a number of medical illnesses as well as bipolar disorder. Activation of inflammatory cytokines is also found to interact with neurocircuits related to neuroticism, a common component of personality disorders. Studies in laboratory animals reveal that inflammatory cytokines: (1) inhibit neurogenesis, which is required in part for antidepressant efficacy, (2) alter glutamate metabolism, which is not a target of conventional antidepressant medications, and (3) increase monoamine transporter activity while decreasing monoamine synthesis, thus counteracting conventional antidepressant action. These data indicate a unique relationship between inflammation and TRD borne out of the impact of inflammatory cytokines on neurobiological pathways that sabotage or circumvent the ability of conventional antidepressants to act effectively. Treatment strategies targeting inflammation may be especially relevant for patients with TRD. doi:10.1016/j.bbi.2011.07.214
212. Dendritic cells in the brain: Distribution and function K. Bulloch The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States Dendritic cells (DC) are immune cells specialized in antigen capture, processing, and presentation to T lymphocytes for the induction of adaptive immunity or tolerance. Since their initial identification and characterization, DC are heterogeneous, consisting of many distinct subpopulations identified by a diverse array of cell surface markers and functions, found in both lymphoid and non-lymphoid tissue, e.g. dermal skin layer, intestine, liver, lungs, kidneys, and the heart. We have identified a heterogeneous population of brain dendritic cells (bDC) within discrete regions of the CNS using the transgenic mouse itgax-eYFP which expresses the eYFP protein under the promoter for the dendritic cell marker, CD11c. EYFP-bDC were characterized in animal models of seizure, stroke, and in the normal aging brain using immunocytochemistry and FACS analysis. EYFPbDC further demonstrated antigen presenting ability following intracranial treatment with the pro-inflammatory cytokine interferon gamma (IFN-g). Using radiation chimeras, we showed that resident eYFP-bDC respond to IVC IFN-g. Ongoing work utilizing wild type vesicular stomatitis virus (VSV) to elicit an encephalitic state after intranasal administration demonstrate several distinct populations of eYFP-bDC that recognize and respond to an active VSV infection. Collectively, our studies indicate that the brain’s milieu influences the population dynamics of DC that respond to pathogens and damage. Understanding the molecular mechanisms that underlay this regulation will lead to the generation of new therapeutic targets in CNS pathophysiology. Support: Peter Deane Trust. doi:10.1016/j.bbi.2011.07.215
213. Protective and damaging effects of mediators of stress and adaptation: Central role of the brain B. McEwen The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA Stress is a condition of the mind and a factor in the expression of disease that differs among individuals and reflects not only major life events, but also the conflicts and pressures of daily life that elevate physiological systems so as to cause a chronic stress burden. This burden reflects the influence of genetic variations: individual life-style habits, such as diet, exercise and substance abuse, and adverse early life experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with the chronic stress burden protect the body in the short-run and promote adaptation, but in the long run the burden of chronic stress causes changes in the body that lead to pathophysiology, as will be illustrated for the immune system and the regions of the brain involved in cognition and emotional regulation. Social ordering in human society is associated with gradients of disease, with an increasing frequency or mortality and morbidity along a gradient of decreasing income and education (socioeconomic status, SES). Although the causes of these gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events, as well as differences in life style, and resulting chronic activation of physiological systems involved in adaptation. Acknowledgments: the MacArthur Foundation Research Network for Socioeconomic Status and Health and the National Council on the Developing Child.
doi:10.1016/j.bbi.2011.07.216
214. Higher levels of depression prior to exercise and greater fatigue post-exercise are associated with a larger decrease in plasmacytoid dendritic cell IFN-alpha production J. Hallam, T. Noble, D. Senchina, M. Kohut Iowa State Univeristy, Kinesiology, 283 Forker, Ames, IA 50011, USA This study examined the effects of long duration exercise on virus-stimulated IFNa production by plasmacytoid dendritic cells (pDC’s), as well as the potential role of psychosocial factors in healthy young adults. Subjects completed the POMS questionnaire, ADACL questionnaire and BECK depression test both before and after exercise. Blood was also collected pre and post exercise. PBMC’s were isolated from whole blood; pDC’s were isolated using magnetic separation/negative selection. The pDC’s were cultured with Influenza A/PR/8/34 H1N1 virus for 18 hours. Supernatants were collected and IFNa production was measured via ELISA. The results showed that subjects reporting the greatest level of fatigue during exercise, or higher scores on depression pre-exercise, had the largest decline in IFNa. Also, subjects with the greatest increase in serum IL6 in response to exercise had the greatest decrease in IFNa. The psychosocial survey results showed a negative correlation between IFNa and tension as measured on both the POMS and ADACL, and a negative correlation with measures of anger and confusion in the ADACL. Higher depression scores pre-exercise were associated with greater increases in IL-6 post-exercise. These findings suggest that prolonged exercise suppresses IFNa production by pDCs, particularly in individuals with the greatest levels of fatigue during exercise.
PNIRS meeting abstracts / Brain, Behavior, and Immunity 25 (2011) S179–S242
depressed patients, approximately one third are treatment resistant. Although the neurobiology of treatment resistant depression (TRD) is poorly understood, a number of factors have been associated with antidepressant non-response including obesity, early life stress, personality disorders, bipolar depression and medical co-morbidity. One pathophysiologic mechanism that may link these factors with TRD is inflammation. In addition to a direct relationship between inflammatory markers and TRD, increased inflammation is associated with depression in obesity, early life stress, and a number of medical illnesses as well as bipolar disorder. Activation of inflammatory cytokines is also found to interact with neurocircuits related to neuroticism, a common component of personality disorders. Studies in laboratory animals reveal that inflammatory cytokines: (1) inhibit neurogenesis, which is required in part for antidepressant efficacy, (2) alter glutamate metabolism, which is not a target of conventional antidepressant medications, and (3) increase monoamine transporter activity while decreasing monoamine synthesis, thus counteracting conventional antidepressant action. These data indicate a unique relationship between inflammation and TRD borne out of the impact of inflammatory cytokines on neurobiological pathways that sabotage or circumvent the ability of conventional antidepressants to act effectively. Treatment strategies targeting inflammation may be especially relevant for patients with TRD. doi:10.1016/j.bbi.2011.07.214
212. Dendritic cells in the brain: Distribution and function K. Bulloch The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States Dendritic cells (DC) are immune cells specialized in antigen capture, processing, and presentation to T lymphocytes for the induction of adaptive immunity or tolerance. Since their initial identification and characterization, DC are heterogeneous, consisting of many distinct subpopulations identified by a diverse array of cell surface markers and functions, found in both lymphoid and non-lymphoid tissue, e.g. dermal skin layer, intestine, liver, lungs, kidneys, and the heart. We have identified a heterogeneous population of brain dendritic cells (bDC) within discrete regions of the CNS using the transgenic mouse itgax-eYFP which expresses the eYFP protein under the promoter for the dendritic cell marker, CD11c. EYFP-bDC were characterized in animal models of seizure, stroke, and in the normal aging brain using immunocytochemistry and FACS analysis. EYFPbDC further demonstrated antigen presenting ability following intracranial treatment with the pro-inflammatory cytokine interferon gamma (IFN-g). Using radiation chimeras, we showed that resident eYFP-bDC respond to IVC IFN-g. Ongoing work utilizing wild type vesicular stomatitis virus (VSV) to elicit an encephalitic state after intranasal administration demonstrate several distinct populations of eYFP-bDC that recognize and respond to an active VSV infection. Collectively, our studies indicate that the brain’s milieu influences the population dynamics of DC that respond to pathogens and damage. Understanding the molecular mechanisms that underlay this regulation will lead to the generation of new therapeutic targets in CNS pathophysiology. Support: Peter Deane Trust. doi:10.1016/j.bbi.2011.07.215
213. Protective and damaging effects of mediators of stress and adaptation: Central role of the brain B. McEwen The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA Stress is a condition of the mind and a factor in the expression of disease that differs among individuals and reflects not only major life events, but also the conflicts and pressures of daily life that elevate physiological systems so as to cause a chronic stress burden. This burden reflects the influence of genetic variations: individual life-style habits, such as diet, exercise and substance abuse, and adverse early life experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with the chronic stress burden protect the body in the short-run and promote adaptation, but in the long run the burden of chronic stress causes changes in the body that lead to pathophysiology, as will be illustrated for the immune system and the regions of the brain involved in cognition and emotional regulation. Social ordering in human society is associated with gradients of disease, with an increasing frequency or mortality and morbidity along a gradient of decreasing income and education (socioeconomic status, SES). Although the causes of these gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events, as well as differences in life style, and resulting chronic activation of physiological systems involved in adaptation. Acknowledgments: the MacArthur Foundation Research Network for Socioeconomic Status and Health and the National Council on the Developing Child.
doi:10.1016/j.bbi.2011.07.216
214. Higher levels of depression prior to exercise and greater fatigue post-exercise are associated with a larger decrease in plasmacytoid dendritic cell IFN-alpha production J. Hallam, T. Noble, D. Senchina, M. Kohut Iowa State Univeristy, Kinesiology, 283 Forker, Ames, IA 50011, USA This study examined the effects of long duration exercise on virus-stimulated IFNa production by plasmacytoid dendritic cells (pDC’s), as well as the potential role of psychosocial factors in healthy young adults. Subjects completed the POMS questionnaire, ADACL questionnaire and BECK depression test both before and after exercise. Blood was also collected pre and post exercise. PBMC’s were isolated from whole blood; pDC’s were isolated using magnetic separation/negative selection. The pDC’s were cultured with Influenza A/PR/8/34 H1N1 virus for 18 hours. Supernatants were collected and IFNa production was measured via ELISA. The results showed that subjects reporting the greatest level of fatigue during exercise, or higher scores on depression pre-exercise, had the largest decline in IFNa. Also, subjects with the greatest increase in serum IL6 in response to exercise had the greatest decrease in IFNa. The psychosocial survey results showed a negative correlation between IFNa and tension as measured on both the POMS and ADACL, and a negative correlation with measures of anger and confusion in the ADACL. Higher depression scores pre-exercise were associated with greater increases in IL-6 post-exercise. These findings suggest that prolonged exercise suppresses IFNa production by pDCs, particularly in individuals with the greatest levels of fatigue during exercise.