- Email: [email protected]
Integrative psychoneuroimmunendocrinological approaches in the interface between stress and depression: A road map to resilience
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Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
Individual difference in mitochondrial function moderate the impact of stress on mental health Tim Emmerzaal 1,∗ , Eva Morava 2 , Richard Rodenburg 3 , Tamas Kozicz 1,2 1 Radboud University Medical Center, Department of Anatomy, Nijmegen, The Netherlands 2 Tulane University, Hayward Genetics Center, New Orleans, LA, USA 3 Radboud University Medical Center, Department of Pediatrics, Nijmegen, The Netherlands E-mail address: [email protected] (T. Emmerzaal).
Stress triggers changes in the brain to maintain/restore homeostasis (allostasis). Allostasis can be considered as a simple energy model that joins the energetic costs of challenges of the environment into a continuum. Hence, balance between cost of adaptation to stress and available energy, viz. mitochondrial function, is crucial for mental health. This together with our results revealing significant individual differences in mitochondrial function both in mice and humans postulate that individual differences in mitochondrial function moderate the impact of stress on mental health. More specifically, in this talk I will argue that suboptimal mitochondrial function is pathogenic in depression. He will present clinical and preclinical evidence in support of individual differences in brain mitochondria efficiency as well as discuss mechanisms how individual differences in mitochondrial efficiency interferes with brain structure and function, increasing vulnerability to stress-related psychopathology. Resolving the relationship between mitochondrial function and the impact of stress on mental health at an individual level has a unique utility in better understanding psychiatric illnesses.
itored stress reactivity and recovery from exposure to a 30-min acute restraint stress (ARS) challenge. Results: HPA axis hyperactivation leading to excessive glucocorticoid (CORT) levels was observed in mice with mitochondrial energy deficiency, whereas mitochondrial oxidative stress led to a blunted CORT response due to adrenal insufficiency. Most mitochondrial defects also caused exaggerated stress-induced hyperglycemia, catecholamines, and circulating IL-6 levels. Of the 26 genes investigated in the hippocampus, the expression of 20 (77%) was significantly modulated by at least one of the mitochondrial defects. Hierarchical clustering and principal component analysis further demonstrated qualitatively and quantitatively unique multi-systemic stress response signature for each mitochondrial defect. Conclusions: Mitochondrial functions modulate key aspects of the physiological stress response. Because dysregulation of the investigated physiological systems is a risk factor for agerelated cognitive and functional decline and mortality in the population, mitochondria-induced multi-systemic dysregulation could represent a heretofore unsuspected mechanism for stress pathophysiology. This presentation will also present the mitochondrial allostatic load (MAL) model, which defines the deleterious structural and functional changes that mitochondria undergo in response chronic stress. http://dx.doi.org/10.1016/j.psyneuen.2016.07.198 Symposium 18: Integrative Psychoneuroimmunoendocrinology Time: Sunday, 11/Sep/2016: 10:15am–11:45am Session Chair: Gustavo Eduardo Tafet
http://dx.doi.org/10.1016/j.psyneuen.2016.07.197
Integrative psychoneuroimmunendocrinological approaches in the interface between stress and depression: A road map to resilience
The role of mitochondria as a modulator of neuroendocrine responses to psychological stress
Gustavo Eduardo Tafet ∗ , Diego Javier Feder, Luis Farji, Silvia Reichenberg
Martin Picard 1,∗ , Meagan McManus 2 , Jason Gray 3 , Carla Nasca 3 , Cynthia Moffatt 4 , Piotrek Kopinsky 2 , Erin Seifert 4 , Bruce McEwen 3 , Douglas Wallace 2
Maimonides University, Argentine Republic, Argentina E-mail address: [email protected] (G.E. Tafet).
1
Columbia University, USA Children’s Hospital of Philadelphia, USA 3 Rockefeller University, New York, USA 4 Thomas Jefferson University, Philadelphia, USA E-mail address: [email protected] (M. Picard). 2
Background: How the organism responds to stress, rather than stressors themselves, is the determinant factor that predispose to disease. All physiological systems involved in the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) and sympathetic–adrenal–medullary (SAM) axes, inflammatory signaling, glucose regulation and gene expression, incur increased energy demand. At the cellular level, this is met by mitochondria, organelles which provide energy and intracellular signals for cellular adaptation. Methods: To evaluate the role of mitochondria in the stress response, we compared multi-systemic stress response profiles among mice with normal mitochondria and four genetic mouse models of mitochondrial dysfunction ranging from energy deficiency to mitochondrial oxidative stress were studied. We mon-
It has been shown that chronic stress plays a critical role in the origin and development of depression, including the longlasting effects of stressful experiences during childhood and the chronic impact of environmental stressors later in life. In this regard, different psychological and neurobiological factors have been involved in this process, where a sustained and prolonged activation of the HPA axis, with the resulting hypercortisolism, represents one of the most consistent observations in chronically stressed patients as well as in the depressive. It has been shown that chronic alteration of the HPA axis may lead to an array of consequences, including hyperactivity and increased reactivity of the amygdala, decreased activity and morphological changes in the hippocampus, and altered neurotransmission, most notably in the serotonergic system. In addition, different endocrine systems and immunological changes have been also observed, all of them contributing to increase the risk to develop depressive symptoms in response to stressful situations. Genetic polymorphisms and epigenetic mechanisms have been also studied, providing additional factors of vulnerability. Preliminary results suggest that these alterations could be controlled or even prevented with the appropriate strategies, therefore contributing to develop resilience in certain
Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
individuals. We propose to present an integrated psychoneuroimmunological model to better understand the interactions between these factors and propose integrated psychopharmacological and psychotherapeutic approaches aimed at improving diagnostic, preventive and therapeutic strategies in vulnerable individuals, therefore contributing to create the basis to develop more resilient individuals. http://dx.doi.org/10.1016/j.psyneuen.2016.07.199 TRAIL, neuroinflammation and neurodegeneration: A paradigm for innovative therapeutic intervention in Alzheimer disease Renato Bernadini 1,∗ , Di Benedetto Giulia 1 , Laurence Lempereur 2 , Oriana Valerio 1 1 University of Catania School of Medicine, Catania, Italy 2 Eli-Lilly Laboratory at the University Hospital, Netherlands E-mail address: [email protected] (R. Bernadini).
TRAIL, a cytokine of the TNF superfamily, potently induces neuronal death during neurodegeneration. Detrimental effects of TRAIL are mediated by its death receptor, DR5. In fact, early immunoneutralization of TRAIL results in rescue of neurons from amyloid-beta (AB)-induced death and preserved cognition, paralleled by silencing of inflammatory molecules in the Alzheimer Disease (AD)3xtransgenic-AD mice brain. Anti-TRAIL treatment mitigates the progressive cognitive decline in the same species, along with decreased volume of the spleens, which in aged animals reach 8–10 times the normal spleen size. To corroborate the hypothesis of a prominent role of TRAIL in the AD neuroinflammatory setting, hippocampal cells from Trail-R-ko mice are resistant to death induced by either AB 1–42 or TRAIL. In addition, immunofluorescence experiments indicate that the expression of activated microglia and astrocyte markers, such as Iba-1 and GFAP, is blunted in Trail-R-ko mice treated stereotaxically with AB 1–42. Consistently, TRAIL immunoreactivity was virtually absent, and decreased expression of interleukin-1 beta, as well as of the phosphorylated form of tau protein, along with reduced activation of
77
caspase-3 was detected in hippocampal homogenates from TrailR-ko mice treated with AB. In conclusion, TRAIL substantially fuels neuroinflammation in murine brain during neurodegeneration, an effect that appears mediated by its DR5 receptor. Similarly, neutralization of TRAIL in aged animals results in improved cognitive decline. Taken together, these data suggest that TRAIL plays a major role in AB-induced neurotoxicity. Finally, the TRAIL system may be regarded as a potential candidate target for innovative therapeutic intervention in AD. http://dx.doi.org/10.1016/j.psyneuen.2016.07.200 Resilience biomarkers in a Latin-American population Andrea López mato ∗ , Tomas Maresca Ipbi, Argentine Republic, Argentina E-mail address: [email protected] (A.L. mato). We are currently undergoing a retrospective study aimed at determining resilience markers. We have included 25 latin subjects who have had 2 or more stressful experiences and have not developed depressive disorders. We have chosen to evaluate several markers in order to fulfill our objective, including: 1-clinical markers (specified by Beck, HAM D and PTSD scale); 2-genetic markers (allelic variances of 5-HTT and BDNF genes); 3-metabolic markers (glycated hemoglobin, lipid profile, waist-hip ratio); 4neuropsychological and cognitive markers (personal evaluations and Stroop and Minessota test); 5-peripherical PNIE markers (cortisol, FUC, DHEA, dehydroepiandrosterone/cortisol ratio and thyroid evaluation, NK cells and CD4/CD8 ratio). The work is not completed but preliminary results will be presented. Identified markers may also be relevant to better understand mechanisms of action of vulnerability to stress or resilience. This is the first review to explore a potential link between resilience biomarkers and mental health in our country. http://dx.doi.org/10.1016/j.psyneuen.2016.07.207
Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
Individual difference in mitochondrial function moderate the impact of stress on mental health Tim Emmerzaal 1,∗ , Eva Morava 2 , Richard Rodenburg 3 , Tamas Kozicz 1,2 1 Radboud University Medical Center, Department of Anatomy, Nijmegen, The Netherlands 2 Tulane University, Hayward Genetics Center, New Orleans, LA, USA 3 Radboud University Medical Center, Department of Pediatrics, Nijmegen, The Netherlands E-mail address: [email protected] (T. Emmerzaal).
Stress triggers changes in the brain to maintain/restore homeostasis (allostasis). Allostasis can be considered as a simple energy model that joins the energetic costs of challenges of the environment into a continuum. Hence, balance between cost of adaptation to stress and available energy, viz. mitochondrial function, is crucial for mental health. This together with our results revealing significant individual differences in mitochondrial function both in mice and humans postulate that individual differences in mitochondrial function moderate the impact of stress on mental health. More specifically, in this talk I will argue that suboptimal mitochondrial function is pathogenic in depression. He will present clinical and preclinical evidence in support of individual differences in brain mitochondria efficiency as well as discuss mechanisms how individual differences in mitochondrial efficiency interferes with brain structure and function, increasing vulnerability to stress-related psychopathology. Resolving the relationship between mitochondrial function and the impact of stress on mental health at an individual level has a unique utility in better understanding psychiatric illnesses.
itored stress reactivity and recovery from exposure to a 30-min acute restraint stress (ARS) challenge. Results: HPA axis hyperactivation leading to excessive glucocorticoid (CORT) levels was observed in mice with mitochondrial energy deficiency, whereas mitochondrial oxidative stress led to a blunted CORT response due to adrenal insufficiency. Most mitochondrial defects also caused exaggerated stress-induced hyperglycemia, catecholamines, and circulating IL-6 levels. Of the 26 genes investigated in the hippocampus, the expression of 20 (77%) was significantly modulated by at least one of the mitochondrial defects. Hierarchical clustering and principal component analysis further demonstrated qualitatively and quantitatively unique multi-systemic stress response signature for each mitochondrial defect. Conclusions: Mitochondrial functions modulate key aspects of the physiological stress response. Because dysregulation of the investigated physiological systems is a risk factor for agerelated cognitive and functional decline and mortality in the population, mitochondria-induced multi-systemic dysregulation could represent a heretofore unsuspected mechanism for stress pathophysiology. This presentation will also present the mitochondrial allostatic load (MAL) model, which defines the deleterious structural and functional changes that mitochondria undergo in response chronic stress. http://dx.doi.org/10.1016/j.psyneuen.2016.07.198 Symposium 18: Integrative Psychoneuroimmunoendocrinology Time: Sunday, 11/Sep/2016: 10:15am–11:45am Session Chair: Gustavo Eduardo Tafet
http://dx.doi.org/10.1016/j.psyneuen.2016.07.197
Integrative psychoneuroimmunendocrinological approaches in the interface between stress and depression: A road map to resilience
The role of mitochondria as a modulator of neuroendocrine responses to psychological stress
Gustavo Eduardo Tafet ∗ , Diego Javier Feder, Luis Farji, Silvia Reichenberg
Martin Picard 1,∗ , Meagan McManus 2 , Jason Gray 3 , Carla Nasca 3 , Cynthia Moffatt 4 , Piotrek Kopinsky 2 , Erin Seifert 4 , Bruce McEwen 3 , Douglas Wallace 2
Maimonides University, Argentine Republic, Argentina E-mail address: [email protected] (G.E. Tafet).
1
Columbia University, USA Children’s Hospital of Philadelphia, USA 3 Rockefeller University, New York, USA 4 Thomas Jefferson University, Philadelphia, USA E-mail address: [email protected] (M. Picard). 2
Background: How the organism responds to stress, rather than stressors themselves, is the determinant factor that predispose to disease. All physiological systems involved in the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) and sympathetic–adrenal–medullary (SAM) axes, inflammatory signaling, glucose regulation and gene expression, incur increased energy demand. At the cellular level, this is met by mitochondria, organelles which provide energy and intracellular signals for cellular adaptation. Methods: To evaluate the role of mitochondria in the stress response, we compared multi-systemic stress response profiles among mice with normal mitochondria and four genetic mouse models of mitochondrial dysfunction ranging from energy deficiency to mitochondrial oxidative stress were studied. We mon-
It has been shown that chronic stress plays a critical role in the origin and development of depression, including the longlasting effects of stressful experiences during childhood and the chronic impact of environmental stressors later in life. In this regard, different psychological and neurobiological factors have been involved in this process, where a sustained and prolonged activation of the HPA axis, with the resulting hypercortisolism, represents one of the most consistent observations in chronically stressed patients as well as in the depressive. It has been shown that chronic alteration of the HPA axis may lead to an array of consequences, including hyperactivity and increased reactivity of the amygdala, decreased activity and morphological changes in the hippocampus, and altered neurotransmission, most notably in the serotonergic system. In addition, different endocrine systems and immunological changes have been also observed, all of them contributing to increase the risk to develop depressive symptoms in response to stressful situations. Genetic polymorphisms and epigenetic mechanisms have been also studied, providing additional factors of vulnerability. Preliminary results suggest that these alterations could be controlled or even prevented with the appropriate strategies, therefore contributing to develop resilience in certain
Abstracts / Psychoneuroendocrinology 71S (2016) 1–77
individuals. We propose to present an integrated psychoneuroimmunological model to better understand the interactions between these factors and propose integrated psychopharmacological and psychotherapeutic approaches aimed at improving diagnostic, preventive and therapeutic strategies in vulnerable individuals, therefore contributing to create the basis to develop more resilient individuals. http://dx.doi.org/10.1016/j.psyneuen.2016.07.199 TRAIL, neuroinflammation and neurodegeneration: A paradigm for innovative therapeutic intervention in Alzheimer disease Renato Bernadini 1,∗ , Di Benedetto Giulia 1 , Laurence Lempereur 2 , Oriana Valerio 1 1 University of Catania School of Medicine, Catania, Italy 2 Eli-Lilly Laboratory at the University Hospital, Netherlands E-mail address: [email protected] (R. Bernadini).
TRAIL, a cytokine of the TNF superfamily, potently induces neuronal death during neurodegeneration. Detrimental effects of TRAIL are mediated by its death receptor, DR5. In fact, early immunoneutralization of TRAIL results in rescue of neurons from amyloid-beta (AB)-induced death and preserved cognition, paralleled by silencing of inflammatory molecules in the Alzheimer Disease (AD)3xtransgenic-AD mice brain. Anti-TRAIL treatment mitigates the progressive cognitive decline in the same species, along with decreased volume of the spleens, which in aged animals reach 8–10 times the normal spleen size. To corroborate the hypothesis of a prominent role of TRAIL in the AD neuroinflammatory setting, hippocampal cells from Trail-R-ko mice are resistant to death induced by either AB 1–42 or TRAIL. In addition, immunofluorescence experiments indicate that the expression of activated microglia and astrocyte markers, such as Iba-1 and GFAP, is blunted in Trail-R-ko mice treated stereotaxically with AB 1–42. Consistently, TRAIL immunoreactivity was virtually absent, and decreased expression of interleukin-1 beta, as well as of the phosphorylated form of tau protein, along with reduced activation of
77
caspase-3 was detected in hippocampal homogenates from TrailR-ko mice treated with AB. In conclusion, TRAIL substantially fuels neuroinflammation in murine brain during neurodegeneration, an effect that appears mediated by its DR5 receptor. Similarly, neutralization of TRAIL in aged animals results in improved cognitive decline. Taken together, these data suggest that TRAIL plays a major role in AB-induced neurotoxicity. Finally, the TRAIL system may be regarded as a potential candidate target for innovative therapeutic intervention in AD. http://dx.doi.org/10.1016/j.psyneuen.2016.07.200 Resilience biomarkers in a Latin-American population Andrea López mato ∗ , Tomas Maresca Ipbi, Argentine Republic, Argentina E-mail address: [email protected] (A.L. mato). We are currently undergoing a retrospective study aimed at determining resilience markers. We have included 25 latin subjects who have had 2 or more stressful experiences and have not developed depressive disorders. We have chosen to evaluate several markers in order to fulfill our objective, including: 1-clinical markers (specified by Beck, HAM D and PTSD scale); 2-genetic markers (allelic variances of 5-HTT and BDNF genes); 3-metabolic markers (glycated hemoglobin, lipid profile, waist-hip ratio); 4neuropsychological and cognitive markers (personal evaluations and Stroop and Minessota test); 5-peripherical PNIE markers (cortisol, FUC, DHEA, dehydroepiandrosterone/cortisol ratio and thyroid evaluation, NK cells and CD4/CD8 ratio). The work is not completed but preliminary results will be presented. Identified markers may also be relevant to better understand mechanisms of action of vulnerability to stress or resilience. This is the first review to explore a potential link between resilience biomarkers and mental health in our country. http://dx.doi.org/10.1016/j.psyneuen.2016.07.207