- Email: [email protected]
50. Exposure to environmental mold affects interleukin-1β expression and survival of newborn neurons
Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52
engraftment (TtoE). Dyads (N = 109) were HSCTp (M (SD) age = 48.2(12.7)) and caregivers (M (SD) age = 52.7(12.6)). Linear regression controlled for clinically relevant patient variables (age, sex, pre-transplant treatment intensity, clinical status). Better caregiver subjective sleep quality (Pittsburgh Sleep Quality Index) and objective sleep efficiency (SE; actigraphy) collected prior to engraftment significantly predicted TtoE (std beta’s = .20 and .30 respectively; p’s < .05). Objective SE remained a significant predictor of TtoE after additionally controlling for sleep medications (std beta = .29; p < .05), explaining an additional 8% of the variance (total R squared = 24%). Further, the timespan of sleep assessment relative to engraftment (M (SD) days = 18.5(12.1)) was controlled for to address the potential bidirectional relationship (e.g., shorter TtoE led to better caregiver sleep), and significant effects of caregiver SE remained (std beta = .18; p < .05). These data highlight potential influences of caregiver self-care, specifically sleep, on HSCTp outcome. Future research should examine potential mediators of this relationship as well as addressing caregivers’ psychological wellbeing and sleep disturbance during the process of HSCT. (Supported by NIH grant CA126971 and PCORI contract CE-1304-6208.) http://dx.doi.org/10.1016/j.bbi.2014.06.068
49. Identification of a rapid, high-capacity influx transporter for CCL11 at the blood–brain barrier in young and aged mice M.A. Erickson a,b,c, Y. Morofuji b,c,d, J.B. Owen b,c,e, W.A. Banks b,c a University of Pennsylvania, Department of Pathology, School of Dental Medicine, 240 S. 40th St., Levy Rm. 312, Philadelphia, PA 19104, USA b University of Washington, USA c Veterans Affairs Puget Sound Health Care System, USA d University of Nagasaki, Japan e University of Kentucky, USA
Increased blood levels of the chemokine CCL11 (eotaxin) in aging inhibit adult hippocampal neurogenesis. However, the precise mechanism by which CCL11 in the circulation exerts this inhibitory function is unclear. We have recently characterized a rapid, high-capacity transport system for CCL11 at the blood–brain barrier (BBB) in young adult mice. This transport system shows biphasic kinetics, with a slow phase preceding a rapid phase of uptake and is not saturated by extra-physiological levels of CCL11. CCL11 was found to bind cellular components in blood, and CCL11 uptake was monophasic with a rate comparable to the fast phase of transport using an in situ brain perfusion technique, which excludes the contribution of blood. To determine whether CCL11 transport is altered at the BBB in aging, we assessed CCL11 transport at a single time point using in situ brain perfusion in mice aged 4, 12, or 20 months. No differences in uptake were observed, suggesting that the transport system for CCL11 at the BBB is unaltered during aging. Therefore, increased levels of CCL11 in blood, such as those observed in aging, may be sufficient to elevate CCL11 levels in the brain and adversely affect neurogenesis. http://dx.doi.org/10.1016/j.bbi.2014.06.069
50. Exposure to environmental mold affects interleukin-1b expression and survival of newborn neurons K. Page a,b, A. Lopez b, E. Normand c, L. Blachorsky b, N. Nassimi b, N. Adams c, T. Roa c, C. Pytte a,b, C. Harding a,c a Graduate Center, CUNY, 365 5th Avenue, Room 6304.01, New York, NY 10016, USA b Queens College, CUNY, USA c Hunter College, CUNY, USA
e15
Mold exposure can cause cognitive impairment. We recently developed a mouse model to determine mechanisms leading to impaired cognition. We found that repeated exposure to the mold Stachybotrys caused deficits in hippocampal memory. We hypothesized that these effects are mediated, in part, by increased inflammation and decreased survival of new neurons. Adult mice were instilled intranasally with low doses of intact mold spores, extracted spore skeletons, or saline vehicle (3x wk/ 6 wks). Extracted spores had toxins removed and proteins denatured. Brains were processed to label the pro-inflammatory cytokine interleukin-1b (Il-1b), immature new neurons (doublecortin) or mature new neurons (bromodeoxyuridine/NeuN) and quantified throughout the dorsomedial dentate gyrus. Earlier, we showed that exposure to both intact and extracted spores resulted in the same memory deficits. Here we found significantly fewer mature new neurons following exposure to intact spores, and fewer young neurons in mice treated with extracted spores. This suggests that intact and extracted spores may induce the same cognitive impairment via different mechanisms. Interestingly, we also found an inverse correlation between numbers of cells expressing Il-1b and mature new neurons, and a positive correlation between cells expressing IL-1b and numbers of young neurons. We suggest that decreased survival of older neurons associated with inflammation results in a compensatory increase in younger neurons. However the increase is insufficient to overcome overall decreased numbers of mature new neurons. http://dx.doi.org/10.1016/j.bbi.2014.06.070
51. Developing a novel animal model of depression to study the role of inflammation in disease progression and in the mechanism of antidepressant action K. Musaelyan, M.T. Egeland, P.A. Zunszain, C.M. Pariante, S. Thuret, C. Fernandes Centre of the Cellular Basis of Behaviour, 125 Coldharbour lane, Institute of Psychiatry, London SE5 9NU, Great Britain and Northern Ireland, UK To study the role of inflammation in depression and in the mechanisms of antidepressant action a valid animal model is required. To develop such a model, we proposed to combine exposure to inflammatory stimulus modelled by peripheral lipopolysaccharide (LPS) injection with an environmental stress-based model of depression – unpredictable chronic mild stress (UCMS) to achieve an immunologically-relevant depression-like phenotype. In a pilot experiment, we treated 8 weeks old male BALB/c mice with 0.33 mg/kg LPS and subsequently exposed them to UCMS for 7 weeks. Fluoxetine-treated groups (10 mg/kg daily) were also included in our experimental design (N = 12). LPS and UCMS exposed mice displayed significant coat state deterioration (UCMS factor H (7) = 37.5, p < 0.0001) and locomotor hyperactivity in a novel arena (UCMS factor F (1,74) = 20.8, p < 0.0001). When coat state was assessed 4 days after the end of UCMS paradigm, the UCMS-only group already displayed signs of recovery with the coat deterioration score indistinguishable from control, while animals exposed to both LPS and UCMS did not show improvement of the coat state. Fluoxetine treatment of the LPS and UCMS exposed group promoted the recovery of the coat state with the coat deterioration score returning to control levels. Future assessment of the neurobiological phenotype (corticosterone response to stress, peripheral cytokines and hippocampal neurogenesis levels) will be presented to allow us to further unravel the neurobiological basis of the observed behavioural changes. http://dx.doi.org/10.1016/j.bbi.2014.06.071
engraftment (TtoE). Dyads (N = 109) were HSCTp (M (SD) age = 48.2(12.7)) and caregivers (M (SD) age = 52.7(12.6)). Linear regression controlled for clinically relevant patient variables (age, sex, pre-transplant treatment intensity, clinical status). Better caregiver subjective sleep quality (Pittsburgh Sleep Quality Index) and objective sleep efficiency (SE; actigraphy) collected prior to engraftment significantly predicted TtoE (std beta’s = .20 and .30 respectively; p’s < .05). Objective SE remained a significant predictor of TtoE after additionally controlling for sleep medications (std beta = .29; p < .05), explaining an additional 8% of the variance (total R squared = 24%). Further, the timespan of sleep assessment relative to engraftment (M (SD) days = 18.5(12.1)) was controlled for to address the potential bidirectional relationship (e.g., shorter TtoE led to better caregiver sleep), and significant effects of caregiver SE remained (std beta = .18; p < .05). These data highlight potential influences of caregiver self-care, specifically sleep, on HSCTp outcome. Future research should examine potential mediators of this relationship as well as addressing caregivers’ psychological wellbeing and sleep disturbance during the process of HSCT. (Supported by NIH grant CA126971 and PCORI contract CE-1304-6208.) http://dx.doi.org/10.1016/j.bbi.2014.06.068
49. Identification of a rapid, high-capacity influx transporter for CCL11 at the blood–brain barrier in young and aged mice M.A. Erickson a,b,c, Y. Morofuji b,c,d, J.B. Owen b,c,e, W.A. Banks b,c a University of Pennsylvania, Department of Pathology, School of Dental Medicine, 240 S. 40th St., Levy Rm. 312, Philadelphia, PA 19104, USA b University of Washington, USA c Veterans Affairs Puget Sound Health Care System, USA d University of Nagasaki, Japan e University of Kentucky, USA
Increased blood levels of the chemokine CCL11 (eotaxin) in aging inhibit adult hippocampal neurogenesis. However, the precise mechanism by which CCL11 in the circulation exerts this inhibitory function is unclear. We have recently characterized a rapid, high-capacity transport system for CCL11 at the blood–brain barrier (BBB) in young adult mice. This transport system shows biphasic kinetics, with a slow phase preceding a rapid phase of uptake and is not saturated by extra-physiological levels of CCL11. CCL11 was found to bind cellular components in blood, and CCL11 uptake was monophasic with a rate comparable to the fast phase of transport using an in situ brain perfusion technique, which excludes the contribution of blood. To determine whether CCL11 transport is altered at the BBB in aging, we assessed CCL11 transport at a single time point using in situ brain perfusion in mice aged 4, 12, or 20 months. No differences in uptake were observed, suggesting that the transport system for CCL11 at the BBB is unaltered during aging. Therefore, increased levels of CCL11 in blood, such as those observed in aging, may be sufficient to elevate CCL11 levels in the brain and adversely affect neurogenesis. http://dx.doi.org/10.1016/j.bbi.2014.06.069
50. Exposure to environmental mold affects interleukin-1b expression and survival of newborn neurons K. Page a,b, A. Lopez b, E. Normand c, L. Blachorsky b, N. Nassimi b, N. Adams c, T. Roa c, C. Pytte a,b, C. Harding a,c a Graduate Center, CUNY, 365 5th Avenue, Room 6304.01, New York, NY 10016, USA b Queens College, CUNY, USA c Hunter College, CUNY, USA
e15
Mold exposure can cause cognitive impairment. We recently developed a mouse model to determine mechanisms leading to impaired cognition. We found that repeated exposure to the mold Stachybotrys caused deficits in hippocampal memory. We hypothesized that these effects are mediated, in part, by increased inflammation and decreased survival of new neurons. Adult mice were instilled intranasally with low doses of intact mold spores, extracted spore skeletons, or saline vehicle (3x wk/ 6 wks). Extracted spores had toxins removed and proteins denatured. Brains were processed to label the pro-inflammatory cytokine interleukin-1b (Il-1b), immature new neurons (doublecortin) or mature new neurons (bromodeoxyuridine/NeuN) and quantified throughout the dorsomedial dentate gyrus. Earlier, we showed that exposure to both intact and extracted spores resulted in the same memory deficits. Here we found significantly fewer mature new neurons following exposure to intact spores, and fewer young neurons in mice treated with extracted spores. This suggests that intact and extracted spores may induce the same cognitive impairment via different mechanisms. Interestingly, we also found an inverse correlation between numbers of cells expressing Il-1b and mature new neurons, and a positive correlation between cells expressing IL-1b and numbers of young neurons. We suggest that decreased survival of older neurons associated with inflammation results in a compensatory increase in younger neurons. However the increase is insufficient to overcome overall decreased numbers of mature new neurons. http://dx.doi.org/10.1016/j.bbi.2014.06.070
51. Developing a novel animal model of depression to study the role of inflammation in disease progression and in the mechanism of antidepressant action K. Musaelyan, M.T. Egeland, P.A. Zunszain, C.M. Pariante, S. Thuret, C. Fernandes Centre of the Cellular Basis of Behaviour, 125 Coldharbour lane, Institute of Psychiatry, London SE5 9NU, Great Britain and Northern Ireland, UK To study the role of inflammation in depression and in the mechanisms of antidepressant action a valid animal model is required. To develop such a model, we proposed to combine exposure to inflammatory stimulus modelled by peripheral lipopolysaccharide (LPS) injection with an environmental stress-based model of depression – unpredictable chronic mild stress (UCMS) to achieve an immunologically-relevant depression-like phenotype. In a pilot experiment, we treated 8 weeks old male BALB/c mice with 0.33 mg/kg LPS and subsequently exposed them to UCMS for 7 weeks. Fluoxetine-treated groups (10 mg/kg daily) were also included in our experimental design (N = 12). LPS and UCMS exposed mice displayed significant coat state deterioration (UCMS factor H (7) = 37.5, p < 0.0001) and locomotor hyperactivity in a novel arena (UCMS factor F (1,74) = 20.8, p < 0.0001). When coat state was assessed 4 days after the end of UCMS paradigm, the UCMS-only group already displayed signs of recovery with the coat deterioration score indistinguishable from control, while animals exposed to both LPS and UCMS did not show improvement of the coat state. Fluoxetine treatment of the LPS and UCMS exposed group promoted the recovery of the coat state with the coat deterioration score returning to control levels. Future assessment of the neurobiological phenotype (corticosterone response to stress, peripheral cytokines and hippocampal neurogenesis levels) will be presented to allow us to further unravel the neurobiological basis of the observed behavioural changes. http://dx.doi.org/10.1016/j.bbi.2014.06.071