- Email: [email protected]
Space as an extraordinary model of Stress research, the role of the ESA Topical Team
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
There is a bidirectional communication between the brain and the gut through the autonomic nervous system (ANS), represented by the sympathetic and parasympathetic nervous systems. The vagus nerve (VN) is a major component of the ANS which plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferents (via the activation of the hypothalamic pituitary adrenal axis) and efferents (via the cholinergic anti-inflammatory pathway; CAP). VN stimulation (VNS) is used for the treatment of drug-resistant epilepsy and depression in humans. We have shown for the first time in rats that chronic low frequency (5Hz) VNS, supposed to activate vagal efferents, has an anti-inflammatory effect in a model of TNBS-colitis, classically used as a model of Crohn’s disease (CD). Consequently, in a translational approach, VNS would be of interest in the treatment of moderate to severe CD. Anti-TNF therapy is presently the gold standard in the treatment of CD but VNS, based on its anti-TNF effect through the CAP, could be an alternative. We are performing a pilot study on VNS in patients with moderate to severe CD. We have implanted 8 patients and presently 6 patients are in remission. Vagal tone, measured by heart rate variability, is improved in most of the patients and we have previously shown that there is an inverse association between vagal tone and TNF-alpha level in CD patients. VNS could also be of interest in other TNF-mediated diseases, such as rheumatoid arthritis and psoriasis, as well as in irritable bowel syndrome.
doi:10.1016/j.autneu.2015.07.272
ABSTRACTS SELECTED FOR PRESENTATION 5.4 Cholecystokinin infused in the celiac and cranial mesenteric arteries reduces food intake and increases Fos-like immunoreactivity in the enteric and the dorsal vagal complex neurons Martha C. Washington, Ayman I. Sayegh Gastroenterology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, USA Cholecystokinin (CCK) is a peptide secreted by the I-cells of the small intestine and evokes a variety of responses e.g. reduction of meal size (MS) and prolongation of the intermeal interval (IMI, time between two consecutive meals). We have shown that the areas supplied by the celiac artery (CA, supplies stomach and upper duodenum) and the cranial mesenteric artery (CMA supplies small and part of the large intestine) contain site of actions controlling the previous feeding responses, MS and IMI length, in free feeding, undisturbed Sprague Dawley rats maintained on normal rat chow. Here, we determined activation of the enteric neurons and dorsal vagal complex (DVC) by two forms of CCK, CCK-8, the most used commercial form and CCK-58, the only endocrine form of the peptide infused in the CA, CMA and the femoral artery (FA, control) prior to the onset of the dark cycle. Sixty minutes following the infusion all rats were sacrificed and Fos-like immunoreactivity (Fos-LI) was quantified in the myenteric and the submucosal plexuses of the duodenum and in the hindbrain areas that control food intake e.g. the dorsal motor nucleus of the vagus (DVC), area postrema (AP) and nucleus tractus solitarius (NTS). We found that CCK-58 infused in the CA and CMA but not in the FA increased Fos-LI in the myenteric and the submucosal plexuses and the DVC. In Conclusion, these results provide further evidence that the areas supplied by the CA and CMA contains sites of action controlling MS and IMI length by CCK-58.
doi:10.1016/j.autneu.2015.07.273
9
5.5 Early suppression of the excessive inflammatory response may attribute to the beneficial effect of vagal nerve stimulation on chronic heart failure Akiko Nishizakia, Keita Sakub, Kenji Sunagawab a Department of Graduate Medical Science of Cardiovascular Medicine b Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, Japan Background: The inflammatory response plays a pivotal role in the pathogenesis of chronic heart failure (CHF). Although vagal nerve stimulation (VNS) improves CHF independent of heart rate reduction, the mechanism that benefits CHF remains unclear. Since VNS exerts the powerful anti-inflammatory effect, we investigated how VNS impacts on the inflammation in the development of CHF after large myocardial infarction (MI) in rats. Methods: In 8 weeks Sprague–Dawley rats, we created large myocardial infarction (MI) and started VNS 2 weeks after MI (CHF: n = 8, VNS: n = 13). We adjusted the intensity of VNS (20Hz) below the level to induce bradycardia. To elucidate the pure impact of VNS on inflammation, we evaluated systemic (blood) and local (heart) inflammatory markers at 3 days after the initiation of VNS. Results: At 3 days, VNS change neither hemodynamic parameters nor plasma BNP as an index of CHF. VNS significantly reduced the invasion of CD 68 positive cells (CHF: 295.1 ± 142.1, VNS: 110.7 ± 59.6 counts/mm2, p b 0.01) and decreased MCP-1 in the left ventricle (LV). In addition, VNS markedly reduced interleukin-1β (IL-1β) in plasma (CHF: 75.7 ± 27.6, VNS: 32.9 ± 6.8 pg/mL, p b 0.01) and heart (CHF: 13.2 ± 4.6, VNS: 9.3 ± 2.4 pg/mg, p b 0.05). TNF-α and IL-6 remained unchanged between two groups. Conclusion: VNS significant attenuates IL-1β production and the invasion of inflammatory cells prior to the improvement of hemodynamics. Early suppression of the excessive inflammatory response may attribute to the beneficial effect of VNS on CHF in the long-term.
doi:10.1016/j.autneu.2015.07.274
SYMPOSIUM 6: STRESS AND IMMUNITY: BRIDGING THE ANS TO EXTREME CONDITIONS OF LIFE 6.1 Space as an extraordinary model of Stress research, the role of the ESA Topical Team A. Choukèr, on behalf of the ESA Topical Team (TT) Stress and Immunology Hospital of the University of Munich, Germany E-mail address: [email protected] (A. Choukèr) During space flight human physiology and health are affected by complex environmental challenges which might be most pronounced by extended periods during interplanetary missions. Adequate immune response is crucial to maintain health. To our knowledge the influence of stressful conditions of psychological or physical nature can activate and/ or paralyse humans’ innate or specific immunity. Previous findings from terrestrial studies as well as from pre -and post space-flight studies and first preliminary data from the ISS indicate a strong interaction between stress-associated, neural and endocrine mediators and the immune system. Moreover, this complex communication among immune cells is also mediated by the ANS, tissue hormones e.g. derived from the cells´ metabolism and other hormone-like substances altogether modulating
10
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
the stress response. The ESA sponsored Topical Team has been working since 2007 to develop integrative theories and suggestions to open up a better understanding of stress - organ interactions with the goal to set -up new preventive or therapeutic strategies to protect from and to treat stress-associated immune and health alterations in space. According to the overall scopes, the TT aims to address and identify-in an interdisciplinary and more holistic approach-the role and impact of stressful conditions occurring in space or in future extra-terrestrial habitats. Also it will be reported how the Topical Team has pursued with other invited international experts the development of technical tools and approaches to help assessing the individual´s homeostasis under stressful condition, always keeping–beyond applications for space- also an application for Earth in the focus as well.
as it is vital to remember both dangerous and favorable situations. However, in case of extremely aversive experiences, increased memory of such experiences can contribute to the development and symptoms of anxiety disorders, such as PTSD or phobias. I will present human studies on the neural basis of emotional memory and will discuss how stress hormones and genetic- and epigenetic variations can affect emotional memory and the risk for anxiety disorders. doi:10.1016/j.autneu.2015.07.277
6.4 Cardiovascular Adaptation to Long Duration Spaceflight
doi:10.1016/j.autneu.2015.07.275 Benjamin D. Livine 6.2 The sympathetic nervous system and HPA axis interact to influence memory: the experimental understanding B. Roozendaal, on behalf of the ESA Topical Team (TT) Stress and Immunology Department of Cognitive Neuroscience, Radboud university medical center and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands Stressful or emotionally arousing experiences are typically well remembered. In my presentation I will describe findings from animals experiments indicating that sympathetic activation and peripheral catecholamines, epinephrine and norepinephrine, as well as hypothalamo-pituitary-adrenal activation enhance the consolidation of memory during stressful or emotionally arousing experiences. In contrast, catecholamines and glucocorticoid hormones impair the retrieval of memory processing. These stress hormones do not uniformly modulate memory of all kinds of information but, rather, preferentially influence the consolidation and retrieval of memory of emotionally arousing information or during emotioally arousing test situations. These findings fit well with extensive evidence from our laboratory indicating that emotional arousal-induced noradrenergic activation within the basolateral complex of the amygdala (BLA) is critically involved in mediating such stress hormone effects on memory consolidation and memory retrieval. Evidence that lesions of the BLA or infusions of a beta-adrenoceptor antagonist into the BLA block the modulatory effects of stress hormone administration on memory suggests that arousal-induced noradrenergic activation within the BLA is a co-requirement in enabling stress hormone effects to modulate memory consolidation. doi:10.1016/j.autneu.2015.07.276
6.3 The sympathetic nervous system and HPA axis interact to influence memory: Clinical implications D. de Quervain, on behalf of the ESA Topical Team (TT) Stress and Immunology Division of Cognitive Neuroscience, University of Basel, Switzerland Enhanced memory for emotional events is a well-recognized phenomenon, which has obvious adaptive value in evolutionary terms,
doi:10.1016/j.autneu.2015.07.278
6.5 Autonomic nervous system under microgravity, and effect of artificial gravity as the countermeasure Satoshi Iwasea, Naoki Nishimuraa, Kunihiko Tanakab, Tadaaki Manob a Department of Physiology, Aichi Medical University, Nagakute 480–1195 b Gifu University of Medical Sciences, Seki 501–3822, Japan E-mail address: [email protected] (Satoshi Iwase) Spaceflight crew members often suffer from space flight deconditioning including neurovestibular disorientation, cardiovascular deconditioning, myatrophy, and bone mineral loss. Several countermeasures have been introduced, but no single measure has been proved to be effective as the countermeasure. We have constructed the short arm centrifuge with ergometer with the radius of 1.4 m because the available space in international space station was reported to the inside of the cylinder with the diameter of 2.8 m. Subjects were required to lay down with supine position. Their legs were raised up to 70 cm high, and there, cycling pedals, which was fixed at the level of leg rotation, were stepped during centrifuge. G-level of 1.4 G with ergometric exercise of 60 W was loaded in the countermeasure group while control group were requested to lie down without exercise. Prescription of countermeasure was set at the AG load with exercise from the 1.4 G at the heart level and 4 – 5 G at the foot level, with ergometric exercise of 60 W in cumulated 30 min per day. Head-down bedrest of −6° was required to 6 subjects as an analogue of microgravity exposure with 2300 kcal/day, and the same amount of water drinking as the urine volume was recommended in the next day. Before and after the bed-rest, several measurements were applied to assess neurovestibular, cardiovascular, musculoskeletal, and bone metabolism, and bedrest studies were carried out comparing the countermeasure and control groups. Orthostatic tolerance was evaluated by determining the anti-G score, measuring the time to the endpoint of centrifugation from 1.0 to 2.0 G with 0.2 steps, and summing up the products of G level and time in seconds. Tilt test was performed to examine the responses to the orthostasis with recording of muscle sympathetic nerve activity by microneurography. Several hormones including renin, angiotensin II, and aldosterone as well as vasopressin were determined. Muscle dimension was determined by applying the MRI to measure the cross-sectional area of quadriceps femoris and gastrocnemius. Muscle function was tested by measuring maximal forces. Bone metabolism was assessed by measuring the urinary and blood levels of bone metabolism including deoxypyridinoline and other markers. As the
There is a bidirectional communication between the brain and the gut through the autonomic nervous system (ANS), represented by the sympathetic and parasympathetic nervous systems. The vagus nerve (VN) is a major component of the ANS which plays a key role in the neuroendocrine-immune axis to maintain homeostasis through its afferents (via the activation of the hypothalamic pituitary adrenal axis) and efferents (via the cholinergic anti-inflammatory pathway; CAP). VN stimulation (VNS) is used for the treatment of drug-resistant epilepsy and depression in humans. We have shown for the first time in rats that chronic low frequency (5Hz) VNS, supposed to activate vagal efferents, has an anti-inflammatory effect in a model of TNBS-colitis, classically used as a model of Crohn’s disease (CD). Consequently, in a translational approach, VNS would be of interest in the treatment of moderate to severe CD. Anti-TNF therapy is presently the gold standard in the treatment of CD but VNS, based on its anti-TNF effect through the CAP, could be an alternative. We are performing a pilot study on VNS in patients with moderate to severe CD. We have implanted 8 patients and presently 6 patients are in remission. Vagal tone, measured by heart rate variability, is improved in most of the patients and we have previously shown that there is an inverse association between vagal tone and TNF-alpha level in CD patients. VNS could also be of interest in other TNF-mediated diseases, such as rheumatoid arthritis and psoriasis, as well as in irritable bowel syndrome.
doi:10.1016/j.autneu.2015.07.272
ABSTRACTS SELECTED FOR PRESENTATION 5.4 Cholecystokinin infused in the celiac and cranial mesenteric arteries reduces food intake and increases Fos-like immunoreactivity in the enteric and the dorsal vagal complex neurons Martha C. Washington, Ayman I. Sayegh Gastroenterology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, USA Cholecystokinin (CCK) is a peptide secreted by the I-cells of the small intestine and evokes a variety of responses e.g. reduction of meal size (MS) and prolongation of the intermeal interval (IMI, time between two consecutive meals). We have shown that the areas supplied by the celiac artery (CA, supplies stomach and upper duodenum) and the cranial mesenteric artery (CMA supplies small and part of the large intestine) contain site of actions controlling the previous feeding responses, MS and IMI length, in free feeding, undisturbed Sprague Dawley rats maintained on normal rat chow. Here, we determined activation of the enteric neurons and dorsal vagal complex (DVC) by two forms of CCK, CCK-8, the most used commercial form and CCK-58, the only endocrine form of the peptide infused in the CA, CMA and the femoral artery (FA, control) prior to the onset of the dark cycle. Sixty minutes following the infusion all rats were sacrificed and Fos-like immunoreactivity (Fos-LI) was quantified in the myenteric and the submucosal plexuses of the duodenum and in the hindbrain areas that control food intake e.g. the dorsal motor nucleus of the vagus (DVC), area postrema (AP) and nucleus tractus solitarius (NTS). We found that CCK-58 infused in the CA and CMA but not in the FA increased Fos-LI in the myenteric and the submucosal plexuses and the DVC. In Conclusion, these results provide further evidence that the areas supplied by the CA and CMA contains sites of action controlling MS and IMI length by CCK-58.
doi:10.1016/j.autneu.2015.07.273
9
5.5 Early suppression of the excessive inflammatory response may attribute to the beneficial effect of vagal nerve stimulation on chronic heart failure Akiko Nishizakia, Keita Sakub, Kenji Sunagawab a Department of Graduate Medical Science of Cardiovascular Medicine b Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, Japan Background: The inflammatory response plays a pivotal role in the pathogenesis of chronic heart failure (CHF). Although vagal nerve stimulation (VNS) improves CHF independent of heart rate reduction, the mechanism that benefits CHF remains unclear. Since VNS exerts the powerful anti-inflammatory effect, we investigated how VNS impacts on the inflammation in the development of CHF after large myocardial infarction (MI) in rats. Methods: In 8 weeks Sprague–Dawley rats, we created large myocardial infarction (MI) and started VNS 2 weeks after MI (CHF: n = 8, VNS: n = 13). We adjusted the intensity of VNS (20Hz) below the level to induce bradycardia. To elucidate the pure impact of VNS on inflammation, we evaluated systemic (blood) and local (heart) inflammatory markers at 3 days after the initiation of VNS. Results: At 3 days, VNS change neither hemodynamic parameters nor plasma BNP as an index of CHF. VNS significantly reduced the invasion of CD 68 positive cells (CHF: 295.1 ± 142.1, VNS: 110.7 ± 59.6 counts/mm2, p b 0.01) and decreased MCP-1 in the left ventricle (LV). In addition, VNS markedly reduced interleukin-1β (IL-1β) in plasma (CHF: 75.7 ± 27.6, VNS: 32.9 ± 6.8 pg/mL, p b 0.01) and heart (CHF: 13.2 ± 4.6, VNS: 9.3 ± 2.4 pg/mg, p b 0.05). TNF-α and IL-6 remained unchanged between two groups. Conclusion: VNS significant attenuates IL-1β production and the invasion of inflammatory cells prior to the improvement of hemodynamics. Early suppression of the excessive inflammatory response may attribute to the beneficial effect of VNS on CHF in the long-term.
doi:10.1016/j.autneu.2015.07.274
SYMPOSIUM 6: STRESS AND IMMUNITY: BRIDGING THE ANS TO EXTREME CONDITIONS OF LIFE 6.1 Space as an extraordinary model of Stress research, the role of the ESA Topical Team A. Choukèr, on behalf of the ESA Topical Team (TT) Stress and Immunology Hospital of the University of Munich, Germany E-mail address: [email protected] (A. Choukèr) During space flight human physiology and health are affected by complex environmental challenges which might be most pronounced by extended periods during interplanetary missions. Adequate immune response is crucial to maintain health. To our knowledge the influence of stressful conditions of psychological or physical nature can activate and/ or paralyse humans’ innate or specific immunity. Previous findings from terrestrial studies as well as from pre -and post space-flight studies and first preliminary data from the ISS indicate a strong interaction between stress-associated, neural and endocrine mediators and the immune system. Moreover, this complex communication among immune cells is also mediated by the ANS, tissue hormones e.g. derived from the cells´ metabolism and other hormone-like substances altogether modulating
10
Abstracts / Autonomic Neuroscience: Basic and Clinical 192 (2015) 1–55
the stress response. The ESA sponsored Topical Team has been working since 2007 to develop integrative theories and suggestions to open up a better understanding of stress - organ interactions with the goal to set -up new preventive or therapeutic strategies to protect from and to treat stress-associated immune and health alterations in space. According to the overall scopes, the TT aims to address and identify-in an interdisciplinary and more holistic approach-the role and impact of stressful conditions occurring in space or in future extra-terrestrial habitats. Also it will be reported how the Topical Team has pursued with other invited international experts the development of technical tools and approaches to help assessing the individual´s homeostasis under stressful condition, always keeping–beyond applications for space- also an application for Earth in the focus as well.
as it is vital to remember both dangerous and favorable situations. However, in case of extremely aversive experiences, increased memory of such experiences can contribute to the development and symptoms of anxiety disorders, such as PTSD or phobias. I will present human studies on the neural basis of emotional memory and will discuss how stress hormones and genetic- and epigenetic variations can affect emotional memory and the risk for anxiety disorders. doi:10.1016/j.autneu.2015.07.277
6.4 Cardiovascular Adaptation to Long Duration Spaceflight
doi:10.1016/j.autneu.2015.07.275 Benjamin D. Livine 6.2 The sympathetic nervous system and HPA axis interact to influence memory: the experimental understanding B. Roozendaal, on behalf of the ESA Topical Team (TT) Stress and Immunology Department of Cognitive Neuroscience, Radboud university medical center and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands Stressful or emotionally arousing experiences are typically well remembered. In my presentation I will describe findings from animals experiments indicating that sympathetic activation and peripheral catecholamines, epinephrine and norepinephrine, as well as hypothalamo-pituitary-adrenal activation enhance the consolidation of memory during stressful or emotionally arousing experiences. In contrast, catecholamines and glucocorticoid hormones impair the retrieval of memory processing. These stress hormones do not uniformly modulate memory of all kinds of information but, rather, preferentially influence the consolidation and retrieval of memory of emotionally arousing information or during emotioally arousing test situations. These findings fit well with extensive evidence from our laboratory indicating that emotional arousal-induced noradrenergic activation within the basolateral complex of the amygdala (BLA) is critically involved in mediating such stress hormone effects on memory consolidation and memory retrieval. Evidence that lesions of the BLA or infusions of a beta-adrenoceptor antagonist into the BLA block the modulatory effects of stress hormone administration on memory suggests that arousal-induced noradrenergic activation within the BLA is a co-requirement in enabling stress hormone effects to modulate memory consolidation. doi:10.1016/j.autneu.2015.07.276
6.3 The sympathetic nervous system and HPA axis interact to influence memory: Clinical implications D. de Quervain, on behalf of the ESA Topical Team (TT) Stress and Immunology Division of Cognitive Neuroscience, University of Basel, Switzerland Enhanced memory for emotional events is a well-recognized phenomenon, which has obvious adaptive value in evolutionary terms,
doi:10.1016/j.autneu.2015.07.278
6.5 Autonomic nervous system under microgravity, and effect of artificial gravity as the countermeasure Satoshi Iwasea, Naoki Nishimuraa, Kunihiko Tanakab, Tadaaki Manob a Department of Physiology, Aichi Medical University, Nagakute 480–1195 b Gifu University of Medical Sciences, Seki 501–3822, Japan E-mail address: [email protected] (Satoshi Iwase) Spaceflight crew members often suffer from space flight deconditioning including neurovestibular disorientation, cardiovascular deconditioning, myatrophy, and bone mineral loss. Several countermeasures have been introduced, but no single measure has been proved to be effective as the countermeasure. We have constructed the short arm centrifuge with ergometer with the radius of 1.4 m because the available space in international space station was reported to the inside of the cylinder with the diameter of 2.8 m. Subjects were required to lay down with supine position. Their legs were raised up to 70 cm high, and there, cycling pedals, which was fixed at the level of leg rotation, were stepped during centrifuge. G-level of 1.4 G with ergometric exercise of 60 W was loaded in the countermeasure group while control group were requested to lie down without exercise. Prescription of countermeasure was set at the AG load with exercise from the 1.4 G at the heart level and 4 – 5 G at the foot level, with ergometric exercise of 60 W in cumulated 30 min per day. Head-down bedrest of −6° was required to 6 subjects as an analogue of microgravity exposure with 2300 kcal/day, and the same amount of water drinking as the urine volume was recommended in the next day. Before and after the bed-rest, several measurements were applied to assess neurovestibular, cardiovascular, musculoskeletal, and bone metabolism, and bedrest studies were carried out comparing the countermeasure and control groups. Orthostatic tolerance was evaluated by determining the anti-G score, measuring the time to the endpoint of centrifugation from 1.0 to 2.0 G with 0.2 steps, and summing up the products of G level and time in seconds. Tilt test was performed to examine the responses to the orthostasis with recording of muscle sympathetic nerve activity by microneurography. Several hormones including renin, angiotensin II, and aldosterone as well as vasopressin were determined. Muscle dimension was determined by applying the MRI to measure the cross-sectional area of quadriceps femoris and gastrocnemius. Muscle function was tested by measuring maximal forces. Bone metabolism was assessed by measuring the urinary and blood levels of bone metabolism including deoxypyridinoline and other markers. As the