- Email: [email protected]
Early-life overnutrition influences spatial memory and hippocampal microgliosis
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
Abstract # 1662 What your monocytes say about your mind and body and why we should listen: Impaired beta2-ARs and GRs may explain obesity-related low-grade inflammation and depressive mood S. Hong, S. Dimitrov, T. Cheng, C. Pruitt, F. Shaikh
e43
to the control group. These data suggest that sleep regulates homeostasis and function of innate immune cells, which are important in the early defence against pathogens. http://dx.doi.org/10.1016/j.bbi.2015.06.162
University of California San Diego, Psychiatry, 9500 Gilman Dr., La Jolla, CA 92093-0804, USA
Abstract # 1666
We have previously reported that low-grade systemic inflammation is associated with compromised immunocompetence in obese individuals. We then showed that an extended recombinant human-TNF treatment of monocytes results in decreased immune response, indicating contribution of chronic inflammation in compromised immunity in obesity. In this study we aimed to further investigate a cellular mechanism of obesity-related inflammation. We hypothesized that the responsivity of monocytes’ beta2 adrenergic (beta2-ARs) and glucocorticoid receptors (GR) to agonists is impaired among the obese. beta2-AR and GR responsivity was examined by assessing intracellular TNF expression in monocytes upon ex vivo LPS-stimulation by flow cytometry with and without isoproterenol (Iso; 10 10–10 8 M) and cortisol (0.1–1 lM), respectively. Plasma IL-1beta, IL-6, TNF, and cortisol levels were determined by immunoassay. Ninety-six asymptomatic individuals participated, and the associations among depressive mood, obesity, and GR responsivity were investigated in a subset (N = 35). Beta2-AR responsivity to Iso in TNF inhibition was smaller among the obese compared to lean individuals (p’s < .05). Furthermore, beta2-AR responsivity was negatively associated with plasma levels of IL-1beta, IL-6 and TNF (p’s < .05). Monocytes’ GR sensitivity to cortisol in regulating TNF production was associated with both obesity (BMI) and somatic depressive mood (Beck Depression Inventory) after controlling for demographic variables (p’s < .05). We propose investigating monocytes as a meaningful and reliable tool in examining the neurohormone-immune link in obesity-related pathology.
The development of a reactive brain endothelium after psychosocial stress C.M. Sawicki, D.B. McKim, E.S. Wohleb, B.L. Jarrett, B.F. Reader, D.M. Norden, J.P. Godbout, J.F. Sheridan
http://dx.doi.org/10.1016/j.bbi.2015.06.161
Abstract # 1665 Impact of sleep on innate immune cells J. Hahn, M. Günter, S. Autenrieth Medizinische Universitätsklinik, Innere Medizin II, Tübingen 72076, Germany Recent studies have shown that sleep has a strong impact on different components of the immune system. Sleep deprivation has been described to affect both humoral as well as cellular immunity. Previously, the NLR ligand muramyldipeptide (MDP), chemically unique cell wall component of all bacteria, has been identified as a sleep-promoting factor in humans and animals, which accumulates during the active period to eventually induce slow wave sleep (SWS). On the other hand, sleep deprivation leads to a lethal sepsis in rats. Here we addressed whether sleep has an impact on the cellular components in blood and spleen and on the outcome of infection. Our results show that sleep deprivation (SD) in mice for up to 6 h led to a significant reduction of cell numbers in the blood in particular of monocytes whereas no effect was seen for PMNs. Further, we observed a reduction of monocytes in the spleen. After intravenous infection of mice with the model pathogen Yersinia enterocolitica, to mimic sepsis, the bacterial load in the spleen of SD-mice was significantly higher one and three days post infection. Also the survival of the SD-Mice was significantly reduced compared
The Ohio State University, 305 W. 12th Ave., Columbus, OH 43210, United States Psychosocial stress is associated with increased inflammation and higher prevalence of mental health disorders like anxiety and depression. Through the activation of several neuroendocrine pathways, psychological stress leads to significant physiological, immunological, and behavioral changes. Repeated social defeat (RSD), a murine model of psychosocial stress, recapitulates many of the behavioral and immunological effects observed in humans, including increased circulating cytokines, immune cell recruitment, and prolonged anxiety-like behavior. The aim of this study was to elucidate the mechanisms underlying stress-induced immune cell trafficking to the brain that leads to the development of a reactive endothelium and behavioral changes. We show that RSD caused an exposure-dependent increase in the gene expression of ICAM1, VCAM1, E-selectin, CXCL1, and CXCL2 in the brain that increased with additional days of stress. RSD-induced ICAM1 and VCAM1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Comparison between enriched CD11b+ cells (microglia/macrophages) and enriched GLAST-1+/CD11b- cells (astrocytes) revealed that RSD increased the gene expression of IL-1 beta, CCL2, and CXCL2 in microglia/macrophages, but not astrocytes. Collectively, these data indicate that critical adhesion mediators are increased in the brain vasculature following RSD. This study begins to establish a mechanism by which the brain facilitates stress-induced immune cell recruitment that may underlie anxiety and mood disorders. http://dx.doi.org/10.1016/j.bbi.2015.06.163
Abstract # 1667 Early-life overnutrition influences spatial memory hippocampal microgliosis S.N. De Luca a, I. Ziko a, J. Nguyen b, J.M. Barwood a, T. Dinan a, L. Sominsky a, T.A. Jenkins b, S.J. Spencer a
and
a RMIT University, School of Health Sciences, Health Innovations Research Institute, PO BOX 71, Melbourne, Victoria 3083, Australia b RMIT University, School of Medical Sciences, Health Innovations Research Institute, Australia
The early life nutritional environment can program hypothalamic microglial proliferation, with a predisposition to a central proinflammatory profile long-term. We hypothesise that long-term microgliosis caused by overnutrition during critical developmental periods extend beyond the hypothalamus into the hippocampus, a pivotal
e44
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
region in memory formation, and that this will disrupt cognition. To test this idea, we manipulated the litter sizes Wistar rat pups were suckled in, ensuring that the pups were raised in litters of 4 (neonatally overfed) or 12 (control). This model of manipulation produces long-term obesity as well as microglial priming in the hypothalamus in the neonatally overfed. Once the rats reached adulthood, we observed the effects of early life overfeeding on cognitive function using the radial arm maze to investigate rat spatial learning and memory. We also examined hippocampal microglial number and density using immunohistochemistry for ionized calcium binding protein (Iba1). Adult rats that were overfed as neonates did not consolidate spatial working and reference memory as efficiently as their control counterparts, despite reaching criterion at the same time. This was accompanied by microgliosis in the dentate gyrus of the hippocampus in the neonatally overfed. These findings suggest early-life diet may influence spatial memory formation at the level of the hippocampus. http://dx.doi.org/10.1016/j.bbi.2015.06.164
Abstract # 1668 Salivary cortisol/CRP ratios indicate treatment response in distressed caregivers I.G. Wheat a, T.S. Sannes a, S.J. Philips a, P.A. Benitez a, C.L. Natvig a, S.K. MikulichGilberson a, T.L. Simoneau b, M.L. Laudenslager a a
University of Colorado Denver, Anschutz Medical Campus, 12700 E. 19th Ave, Aurora, CO 80045, United States b Colorado Blood Cancer Institute, Presbyterian/St. Luke’s Medical Center, Denver, CO, United States Psychological stress is not completely understood with relation to physiologic stress, such as inflammation and the HPA axis. Dysregulation between the HPA axis and inflammation can be estimated using a ratio of cortisol/C-reactive protein (Cort/CRP). We recently demonstrated that Cort/CRP is related to psychological variables in distressed caregivers, but is this ratio related to treatment response to an 8-session individual cognitive behavioral stress management (CBSM) intervention? 106 caregivers (75% women) of patients undergoing allogeneic stem cell transplant (M age = 51.6; SD = 11.9 years) provided one blood sample prior to transplant as well as contemporaneous diurnal saliva samples for assessing cortisol across 3 days for calculation of area under the curve (AUCg). CRP and Cortisol were assessed by EIA. Change scores were calculated from baseline to following CBSM for several psychological measures: depression (CESD), anxiety (StaiS), and perceived stress (PSS). Regression analyses revealed a significant interaction between Cort/CRP and treatment compared to treatment as usual in regards to CESD (b = .413; p = .05), and StaiS (b = .331; p = < .05), but not for PSS (b = .068; p=.682), such that a lower Cort/CRP ratio was related to a greater decrease in CESD and StaiS scores following CBSM. Diurnal salivary cortisol represented as AUCg may be useful in examining Cortisol/CRP. Caregivers with a lower cortisol/CRP may display greater psychological improvement with CBSM intervention. (Funding from NIH CA126971 (MLL); T32AG044296 (TS): DA034604 (SMG) and PCORI CE13046208 (MLL). http://dx.doi.org/10.1016/j.bbi.2015.06.165
Abstract # 1669 Developmental influences on schizophrenia-like cognitive and neurophysiological outcomes in a rat model of maternal immune challenge L. Harms a,d, C. Meehan a,d, K. Zavitsanou b,c,d, R. Fulham a,d, A. Wong a, J. Todd a,d, U. Schall a,d, C. Shannon Weickert b,c,d, P. Michie a,d, D. Hodgson a,d a School of Psychology, University of Newcastle, University Drive, Callaghan, NSW, 2308, USA b Neuroscience Research Australia c University of New South Wales d Schizophrenia Research Institute
The developing brain is sensitive to early-life insults, which can increase the risk of neuropsychiatric disorders such as schizophrenia. Maternal immune system activation during gestation via infection is a known risk factor for schizophrenia. Here we examine the role of early-life immune activation on schizophrenia-related behavioural and electrophysiological outcomes. Pregnant Wistar rats were injected with the viral mimic, Poly(I:C) or vehicle at either gestational day (GD) 10 or GD19. Adult offspring were examined for behaviour (prepulse inhibition (PPI) and working memory) and electrophysiology (generation 50Hz auditory steady-state responses (aSSRs)).Brain tissue was examined for NMDA receptor (NMDAR) binding. Rats exposed to Poly(I:C) at GD10 were found to exhibit reduced PPI, whereas those exposed to Poly(I:C) during late gestation exhibited working memory impairments. In addition, late gestation-exposed rats exhibited reduced power of 50Hz aSSRs, indicating an impaired ability to generate neural oscillations in the high-frequency (gamma) range. Adult offspring exposed to Poly(I:C) on GD19 had increased binding to the NMDAR2A subunit and the NMDAR channel in the hippocampus. Maternal immune activation via a viral mimic was sufficient to alter the trajectory of brain development such that there were long-term impacts of several behavioural and electrophysiological outcomes in adulthood. Several of the behavioural and electrophysiological changes identified here are also found in patients with schizophrenia, indicating that the Maternal Immune Activated rat may model aspects of the disorder. http://dx.doi.org/10.1016/j.bbi.2015.06.166
Abstract # 1670 Sleep compared to nocturnal wakefulness reduces the number of various T cell subsets in human blood L. Besedovsky a, S. Dimitrov a, J. Born a, T. Lange b a Department of Medical Psychology and Behavioral Neurobiology, University of Tuebingen, Otfried-Müller-Straße 25, Tübingen, Germany b Department of Internal Medicine, University of Luebeck, Luebeck, Germany
Circulating T cells show circadian rhythms, the direction and extent of which depend on the specific subset. Naïve and memory T cells peak during nocturnal sleep, whereas cytotoxic effector T cells show an opposite rhythm with highest numbers during daytime. In the current study, we were interested in how sleep affects these different circadian rhythms and therefore measured 8 T cell subsets (naïve, central memory, effector memory, and effector T-helper
Abstract # 1662 What your monocytes say about your mind and body and why we should listen: Impaired beta2-ARs and GRs may explain obesity-related low-grade inflammation and depressive mood S. Hong, S. Dimitrov, T. Cheng, C. Pruitt, F. Shaikh
e43
to the control group. These data suggest that sleep regulates homeostasis and function of innate immune cells, which are important in the early defence against pathogens. http://dx.doi.org/10.1016/j.bbi.2015.06.162
University of California San Diego, Psychiatry, 9500 Gilman Dr., La Jolla, CA 92093-0804, USA
Abstract # 1666
We have previously reported that low-grade systemic inflammation is associated with compromised immunocompetence in obese individuals. We then showed that an extended recombinant human-TNF treatment of monocytes results in decreased immune response, indicating contribution of chronic inflammation in compromised immunity in obesity. In this study we aimed to further investigate a cellular mechanism of obesity-related inflammation. We hypothesized that the responsivity of monocytes’ beta2 adrenergic (beta2-ARs) and glucocorticoid receptors (GR) to agonists is impaired among the obese. beta2-AR and GR responsivity was examined by assessing intracellular TNF expression in monocytes upon ex vivo LPS-stimulation by flow cytometry with and without isoproterenol (Iso; 10 10–10 8 M) and cortisol (0.1–1 lM), respectively. Plasma IL-1beta, IL-6, TNF, and cortisol levels were determined by immunoassay. Ninety-six asymptomatic individuals participated, and the associations among depressive mood, obesity, and GR responsivity were investigated in a subset (N = 35). Beta2-AR responsivity to Iso in TNF inhibition was smaller among the obese compared to lean individuals (p’s < .05). Furthermore, beta2-AR responsivity was negatively associated with plasma levels of IL-1beta, IL-6 and TNF (p’s < .05). Monocytes’ GR sensitivity to cortisol in regulating TNF production was associated with both obesity (BMI) and somatic depressive mood (Beck Depression Inventory) after controlling for demographic variables (p’s < .05). We propose investigating monocytes as a meaningful and reliable tool in examining the neurohormone-immune link in obesity-related pathology.
The development of a reactive brain endothelium after psychosocial stress C.M. Sawicki, D.B. McKim, E.S. Wohleb, B.L. Jarrett, B.F. Reader, D.M. Norden, J.P. Godbout, J.F. Sheridan
http://dx.doi.org/10.1016/j.bbi.2015.06.161
Abstract # 1665 Impact of sleep on innate immune cells J. Hahn, M. Günter, S. Autenrieth Medizinische Universitätsklinik, Innere Medizin II, Tübingen 72076, Germany Recent studies have shown that sleep has a strong impact on different components of the immune system. Sleep deprivation has been described to affect both humoral as well as cellular immunity. Previously, the NLR ligand muramyldipeptide (MDP), chemically unique cell wall component of all bacteria, has been identified as a sleep-promoting factor in humans and animals, which accumulates during the active period to eventually induce slow wave sleep (SWS). On the other hand, sleep deprivation leads to a lethal sepsis in rats. Here we addressed whether sleep has an impact on the cellular components in blood and spleen and on the outcome of infection. Our results show that sleep deprivation (SD) in mice for up to 6 h led to a significant reduction of cell numbers in the blood in particular of monocytes whereas no effect was seen for PMNs. Further, we observed a reduction of monocytes in the spleen. After intravenous infection of mice with the model pathogen Yersinia enterocolitica, to mimic sepsis, the bacterial load in the spleen of SD-mice was significantly higher one and three days post infection. Also the survival of the SD-Mice was significantly reduced compared
The Ohio State University, 305 W. 12th Ave., Columbus, OH 43210, United States Psychosocial stress is associated with increased inflammation and higher prevalence of mental health disorders like anxiety and depression. Through the activation of several neuroendocrine pathways, psychological stress leads to significant physiological, immunological, and behavioral changes. Repeated social defeat (RSD), a murine model of psychosocial stress, recapitulates many of the behavioral and immunological effects observed in humans, including increased circulating cytokines, immune cell recruitment, and prolonged anxiety-like behavior. The aim of this study was to elucidate the mechanisms underlying stress-induced immune cell trafficking to the brain that leads to the development of a reactive endothelium and behavioral changes. We show that RSD caused an exposure-dependent increase in the gene expression of ICAM1, VCAM1, E-selectin, CXCL1, and CXCL2 in the brain that increased with additional days of stress. RSD-induced ICAM1 and VCAM1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Comparison between enriched CD11b+ cells (microglia/macrophages) and enriched GLAST-1+/CD11b- cells (astrocytes) revealed that RSD increased the gene expression of IL-1 beta, CCL2, and CXCL2 in microglia/macrophages, but not astrocytes. Collectively, these data indicate that critical adhesion mediators are increased in the brain vasculature following RSD. This study begins to establish a mechanism by which the brain facilitates stress-induced immune cell recruitment that may underlie anxiety and mood disorders. http://dx.doi.org/10.1016/j.bbi.2015.06.163
Abstract # 1667 Early-life overnutrition influences spatial memory hippocampal microgliosis S.N. De Luca a, I. Ziko a, J. Nguyen b, J.M. Barwood a, T. Dinan a, L. Sominsky a, T.A. Jenkins b, S.J. Spencer a
and
a RMIT University, School of Health Sciences, Health Innovations Research Institute, PO BOX 71, Melbourne, Victoria 3083, Australia b RMIT University, School of Medical Sciences, Health Innovations Research Institute, Australia
The early life nutritional environment can program hypothalamic microglial proliferation, with a predisposition to a central proinflammatory profile long-term. We hypothesise that long-term microgliosis caused by overnutrition during critical developmental periods extend beyond the hypothalamus into the hippocampus, a pivotal
e44
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
region in memory formation, and that this will disrupt cognition. To test this idea, we manipulated the litter sizes Wistar rat pups were suckled in, ensuring that the pups were raised in litters of 4 (neonatally overfed) or 12 (control). This model of manipulation produces long-term obesity as well as microglial priming in the hypothalamus in the neonatally overfed. Once the rats reached adulthood, we observed the effects of early life overfeeding on cognitive function using the radial arm maze to investigate rat spatial learning and memory. We also examined hippocampal microglial number and density using immunohistochemistry for ionized calcium binding protein (Iba1). Adult rats that were overfed as neonates did not consolidate spatial working and reference memory as efficiently as their control counterparts, despite reaching criterion at the same time. This was accompanied by microgliosis in the dentate gyrus of the hippocampus in the neonatally overfed. These findings suggest early-life diet may influence spatial memory formation at the level of the hippocampus. http://dx.doi.org/10.1016/j.bbi.2015.06.164
Abstract # 1668 Salivary cortisol/CRP ratios indicate treatment response in distressed caregivers I.G. Wheat a, T.S. Sannes a, S.J. Philips a, P.A. Benitez a, C.L. Natvig a, S.K. MikulichGilberson a, T.L. Simoneau b, M.L. Laudenslager a a
University of Colorado Denver, Anschutz Medical Campus, 12700 E. 19th Ave, Aurora, CO 80045, United States b Colorado Blood Cancer Institute, Presbyterian/St. Luke’s Medical Center, Denver, CO, United States Psychological stress is not completely understood with relation to physiologic stress, such as inflammation and the HPA axis. Dysregulation between the HPA axis and inflammation can be estimated using a ratio of cortisol/C-reactive protein (Cort/CRP). We recently demonstrated that Cort/CRP is related to psychological variables in distressed caregivers, but is this ratio related to treatment response to an 8-session individual cognitive behavioral stress management (CBSM) intervention? 106 caregivers (75% women) of patients undergoing allogeneic stem cell transplant (M age = 51.6; SD = 11.9 years) provided one blood sample prior to transplant as well as contemporaneous diurnal saliva samples for assessing cortisol across 3 days for calculation of area under the curve (AUCg). CRP and Cortisol were assessed by EIA. Change scores were calculated from baseline to following CBSM for several psychological measures: depression (CESD), anxiety (StaiS), and perceived stress (PSS). Regression analyses revealed a significant interaction between Cort/CRP and treatment compared to treatment as usual in regards to CESD (b = .413; p = .05), and StaiS (b = .331; p = < .05), but not for PSS (b = .068; p=.682), such that a lower Cort/CRP ratio was related to a greater decrease in CESD and StaiS scores following CBSM. Diurnal salivary cortisol represented as AUCg may be useful in examining Cortisol/CRP. Caregivers with a lower cortisol/CRP may display greater psychological improvement with CBSM intervention. (Funding from NIH CA126971 (MLL); T32AG044296 (TS): DA034604 (SMG) and PCORI CE13046208 (MLL). http://dx.doi.org/10.1016/j.bbi.2015.06.165
Abstract # 1669 Developmental influences on schizophrenia-like cognitive and neurophysiological outcomes in a rat model of maternal immune challenge L. Harms a,d, C. Meehan a,d, K. Zavitsanou b,c,d, R. Fulham a,d, A. Wong a, J. Todd a,d, U. Schall a,d, C. Shannon Weickert b,c,d, P. Michie a,d, D. Hodgson a,d a School of Psychology, University of Newcastle, University Drive, Callaghan, NSW, 2308, USA b Neuroscience Research Australia c University of New South Wales d Schizophrenia Research Institute
The developing brain is sensitive to early-life insults, which can increase the risk of neuropsychiatric disorders such as schizophrenia. Maternal immune system activation during gestation via infection is a known risk factor for schizophrenia. Here we examine the role of early-life immune activation on schizophrenia-related behavioural and electrophysiological outcomes. Pregnant Wistar rats were injected with the viral mimic, Poly(I:C) or vehicle at either gestational day (GD) 10 or GD19. Adult offspring were examined for behaviour (prepulse inhibition (PPI) and working memory) and electrophysiology (generation 50Hz auditory steady-state responses (aSSRs)).Brain tissue was examined for NMDA receptor (NMDAR) binding. Rats exposed to Poly(I:C) at GD10 were found to exhibit reduced PPI, whereas those exposed to Poly(I:C) during late gestation exhibited working memory impairments. In addition, late gestation-exposed rats exhibited reduced power of 50Hz aSSRs, indicating an impaired ability to generate neural oscillations in the high-frequency (gamma) range. Adult offspring exposed to Poly(I:C) on GD19 had increased binding to the NMDAR2A subunit and the NMDAR channel in the hippocampus. Maternal immune activation via a viral mimic was sufficient to alter the trajectory of brain development such that there were long-term impacts of several behavioural and electrophysiological outcomes in adulthood. Several of the behavioural and electrophysiological changes identified here are also found in patients with schizophrenia, indicating that the Maternal Immune Activated rat may model aspects of the disorder. http://dx.doi.org/10.1016/j.bbi.2015.06.166
Abstract # 1670 Sleep compared to nocturnal wakefulness reduces the number of various T cell subsets in human blood L. Besedovsky a, S. Dimitrov a, J. Born a, T. Lange b a Department of Medical Psychology and Behavioral Neurobiology, University of Tuebingen, Otfried-Müller-Straße 25, Tübingen, Germany b Department of Internal Medicine, University of Luebeck, Luebeck, Germany
Circulating T cells show circadian rhythms, the direction and extent of which depend on the specific subset. Naïve and memory T cells peak during nocturnal sleep, whereas cytotoxic effector T cells show an opposite rhythm with highest numbers during daytime. In the current study, we were interested in how sleep affects these different circadian rhythms and therefore measured 8 T cell subsets (naïve, central memory, effector memory, and effector T-helper