The Experts below are selected from a list of 162 Experts worldwide ranked by ideXlab platform

Vasiliki Michopoulos - One of the best experts on this subject based on the ideXlab platform.

  • Social history and exposure to pathogen signals modulate Social status effects on gene regulation in rhesus macaques
    Proceedings of the National Academy of Sciences of the United States of America, 2020
    Co-Authors: Joaquin Sanz, Paul L Maurizio, Noah Snydermackler, Noah D Simons, Tawni Voyles, Jordan N Kohn, Vasiliki Michopoulos, Mark L Wilson, Jenny Tung
    Abstract:

    Social experience is an important predictor of disease susceptibility and survival in humans and other Social mammals. Chronic Social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term Social status in female rhesus macaques to show that Social Subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to Social status at the time of sampling, but also to Social history (i.e., past Social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current Social status than those who climbed the Social hierarchy. Taken together, our results indicate that the effects of Social status on immune cell gene expression depend on pathogen exposure, pathogen type, and Social history-in support of Social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

  • Social history and exposure to pathogen signals modulate Social status effects on gene regulation in rhesus macaques
    bioRxiv, 2019
    Co-Authors: Joaquin Sanz, Paul L Maurizio, Noah Snydermackler, Noah D Simons, Tawni Voyles, Jordan N Kohn, Vasiliki Michopoulos, Mark L Wilson, Jenny Tung
    Abstract:

    Social experiences are an important predictor of disease susceptibility and survival in humans and other Social mammals. Chronic Social stress is thought to generate a pro-inflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term Social status in female rhesus macaques to show that Social Subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-kB-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-kB and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to Social status at the time of sampling, but also to Social history (i.e., past Social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current Social status than those who climbed the Social hierarchy. Together, our results indicate that the effects of Social status on immune cell gene expression depend on pathogen exposure, pathogen type, and Social history; in support of Social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

  • Social Subordination stress and serotonin transporter polymorphisms associations with brain white matter tract integrity and behavior in juvenile female macaques
    Cerebral Cortex, 2014
    Co-Authors: Vasiliki Michopoulos, Jodi R Godfrey, Mar M Sanchez, Mark E Wilson, Brittany R Howell, David A Gutman, Xiaodong Zhang, Govind Nair
    Abstract:

    We examined the relationship between Social rank and brain white matter (WM) microstructure, and socioemotional behavior, and its modulation by serotonin (5HT) transporter (5HTT) polymorphisms in prepubertal female macaques. Using diffusion tensor imaging and tract-based spatial statistics, Social status differences were found in medial prefrontal cortex (mPFC) WM and cortico-thalamic tracts, with subordinates showing higher WM structural integrity (measured as fractional anisotropy, FA) than dominant animals. 5HTT genotype-related differences were detected in the posterior limb of the internal capsule, where s-variants had higher FA than l/l animals. Status by 5HTT interaction effects were found in (1) external capsule (middle longitudinal fasciculus), (2) parietal WM, and (3) short-range PFC tracts, with opposite effects in dominant and subordinate animals. In most regions showing FA differences, opposite differences were detected in radial diffusivity, but none in axial diffusivity, suggesting that differences in tract integrity likely involve differences in myelin. These findings highlight that differences in Social rank are associated with differences in WM structural integrity in juveniles, particularly in tracts connecting prefrontal, sensory processing, motor and association regions, sometimes modulated by 5HTT genotype. Differences in these tracts were associated with increased emotional reactivity in subordinates, particularly with higher submissive and fear behaviors.

  • crh receptor antagonism reverses the effect of Social Subordination upon central gabaa receptor binding in estradiol treated ovariectomized female rhesus monkeys
    Neuroscience, 2013
    Co-Authors: Vasiliki Michopoulos, Mar M Sanchez, Donna Toufexis, Molly Embree, Kathy Reding, John R Votaw, Ronald J Voll
    Abstract:

    Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social Subordination in Socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychoSocial stress of Subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using (18)F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to Socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of Social Subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.

  • Social Subordination impairs hypothalamic pituitary adrenal function in female rhesus monkeys
    Hormones and Behavior, 2012
    Co-Authors: Vasiliki Michopoulos, Katherine M Reding, Mark E Wilson, Donna Toufexis
    Abstract:

    Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) Social groups regardless of group size. As a consequence of their low Social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic-pituitary-adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether Social Subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that Social Subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute Social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following Social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychoSocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies.

Mark E Wilson - One of the best experts on this subject based on the ideXlab platform.

  • Social Subordination alters estradiol induced changes in cortico limbic brain volumes in adult female rhesus monkeys
    Psychoneuroendocrinology, 2020
    Co-Authors: Katherine M Reding, Mar M Sanchez, Mark E Wilson, Donna Toufexis, Martin M Styner
    Abstract:

    Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17β-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of Social Subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of Social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic Social stress to modulate these effects on brain structure.

  • effects of Social Subordination and oestradiol on resting state amygdala functional connectivity in adult female rhesus monkeys
    Journal of Neuroendocrinology, 2020
    Co-Authors: Katherine M Reding, Mark E Wilson, Donna Toufexis, David Grayson, Oscar Mirandadominguez, Siddarth Ray, Damien A Fair, Mar M Sanchez
    Abstract:

    Preclinical studies demonstrate that chronic stress modulates the effects of oestradiol (E2) on behaviour through the modification of the amygdala and the medial prefrontal cortex (mPFC) neuronal structure. Clinical studies suggest that alterations in amygdala functional connectivity (FC) with the mPFC may be associated with stress-related phenotypes, including mood and anxiety disorders. Thus, identifying the effects of stress and E2 on amygdala-mPFC circuits is critical for understanding the neurobiology underpinning the vulnerability to stress-related disorders in women. In the present study, we used a well-validated rhesus monkey model of chronic psychoSocial stress (subordinate Social rank) to examine effects of E2 on subordinate (SUB) (i.e. high stress) and dominant (DOM) (i.e. low stress) female resting-state amygdala FC with the mPFC and with the whole-brain. In the non-E2 treatment control condition, SUB was associated with stronger left amygdala FC to subgenual cingulate (Brodmann area [BA] 25: BA25), a region implicated in several psychopathologies in people. In SUB females, E2 treatment strengthened right amygdala-BA25 FC, induced a net positive amygdala-visual cortex FC that was positively associated with frequency of submissive behaviours, and weakened positive amygdala-para/hippocampus FC. Our findings show that subordinate Social rank alters amygdala FC and the impact of E2 on amygdala FC with BA25 and with regions involved in visual processing and memory encoding.

  • an introduction to the female macaque model of Social Subordination stress
    2016
    Co-Authors: Mark E Wilson
    Abstract:

    The use of Socially house macaque monkeys as a translational model of Social stressor exposure in humans is described as an introduction to the chapters in this volume. These macaque models are presented in relation to other animal models designed to determine how Social stressors impact health outcomes for people. While a number of similarities exist, several advantages of the macaque model are apparent. The dominance hierarchy in macaques is defined by matrilineal relations and is thus female-based, providing an important opportunity to study stress-induced disorders in females. Because infants assume the rank of their mothers, it is possible to study the impact of continuous stressor exposure on neurobehavioral development in animals showing a protracted period of development experienced by children. In addition to studies with large breeding groups of macaques in free-ranging or captive environments, small groups can be safely formed with unfamiliar animals, even balancing group composition by previous Social history and specific gene polymorphisms. Furthermore, this strategy allows for groups to be rearranged to assess acute Social instability or the lasting effects of acquiring a new rank. Finally, given the phylogenetic closeness of Old World monkeys to humans compared to nonprimate mammals, brain regions, such as the prefrontal cortex, that govern executive control over emotional behavior and stress responsivity show considerable structural similarity between macaques and humans. Macaque models may be particularly useful in defining how stress accumulation adversely affects health outcomes in people.

  • Social Subordination stress and serotonin transporter polymorphisms associations with brain white matter tract integrity and behavior in juvenile female macaques
    Cerebral Cortex, 2014
    Co-Authors: Vasiliki Michopoulos, Jodi R Godfrey, Mar M Sanchez, Mark E Wilson, Brittany R Howell, David A Gutman, Xiaodong Zhang, Govind Nair
    Abstract:

    We examined the relationship between Social rank and brain white matter (WM) microstructure, and socioemotional behavior, and its modulation by serotonin (5HT) transporter (5HTT) polymorphisms in prepubertal female macaques. Using diffusion tensor imaging and tract-based spatial statistics, Social status differences were found in medial prefrontal cortex (mPFC) WM and cortico-thalamic tracts, with subordinates showing higher WM structural integrity (measured as fractional anisotropy, FA) than dominant animals. 5HTT genotype-related differences were detected in the posterior limb of the internal capsule, where s-variants had higher FA than l/l animals. Status by 5HTT interaction effects were found in (1) external capsule (middle longitudinal fasciculus), (2) parietal WM, and (3) short-range PFC tracts, with opposite effects in dominant and subordinate animals. In most regions showing FA differences, opposite differences were detected in radial diffusivity, but none in axial diffusivity, suggesting that differences in tract integrity likely involve differences in myelin. These findings highlight that differences in Social rank are associated with differences in WM structural integrity in juveniles, particularly in tracts connecting prefrontal, sensory processing, motor and association regions, sometimes modulated by 5HTT genotype. Differences in these tracts were associated with increased emotional reactivity in subordinates, particularly with higher submissive and fear behaviors.

  • Social Subordination impairs hypothalamic pituitary adrenal function in female rhesus monkeys
    Hormones and Behavior, 2012
    Co-Authors: Vasiliki Michopoulos, Katherine M Reding, Mark E Wilson, Donna Toufexis
    Abstract:

    Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) Social groups regardless of group size. As a consequence of their low Social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic-pituitary-adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether Social Subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that Social Subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute Social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following Social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychoSocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies.

Mar M Sanchez - One of the best experts on this subject based on the ideXlab platform.

  • Social Subordination alters estradiol induced changes in cortico limbic brain volumes in adult female rhesus monkeys
    Psychoneuroendocrinology, 2020
    Co-Authors: Katherine M Reding, Mar M Sanchez, Mark E Wilson, Donna Toufexis, Martin M Styner
    Abstract:

    Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17β-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of Social Subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of Social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic Social stress to modulate these effects on brain structure.

  • effects of Social Subordination and oestradiol on resting state amygdala functional connectivity in adult female rhesus monkeys
    Journal of Neuroendocrinology, 2020
    Co-Authors: Katherine M Reding, Mark E Wilson, Donna Toufexis, David Grayson, Oscar Mirandadominguez, Siddarth Ray, Damien A Fair, Mar M Sanchez
    Abstract:

    Preclinical studies demonstrate that chronic stress modulates the effects of oestradiol (E2) on behaviour through the modification of the amygdala and the medial prefrontal cortex (mPFC) neuronal structure. Clinical studies suggest that alterations in amygdala functional connectivity (FC) with the mPFC may be associated with stress-related phenotypes, including mood and anxiety disorders. Thus, identifying the effects of stress and E2 on amygdala-mPFC circuits is critical for understanding the neurobiology underpinning the vulnerability to stress-related disorders in women. In the present study, we used a well-validated rhesus monkey model of chronic psychoSocial stress (subordinate Social rank) to examine effects of E2 on subordinate (SUB) (i.e. high stress) and dominant (DOM) (i.e. low stress) female resting-state amygdala FC with the mPFC and with the whole-brain. In the non-E2 treatment control condition, SUB was associated with stronger left amygdala FC to subgenual cingulate (Brodmann area [BA] 25: BA25), a region implicated in several psychopathologies in people. In SUB females, E2 treatment strengthened right amygdala-BA25 FC, induced a net positive amygdala-visual cortex FC that was positively associated with frequency of submissive behaviours, and weakened positive amygdala-para/hippocampus FC. Our findings show that subordinate Social rank alters amygdala FC and the impact of E2 on amygdala FC with BA25 and with regions involved in visual processing and memory encoding.

  • effects of Social Subordination on macaque neurobehavioral outcomes focus on neurodevelopment
    2016
    Co-Authors: Jodi R Godfrey, Melanie Pincus, Mar M Sanchez
    Abstract:

    Social stress during childhood and adolescence leads to alterations in emotional and stress reactivity and neuroendocrine function. These negative experiences have also been associated with alterations in brain development that lead to psychopathology, such as anxiety and depression, which are more prevalent in females than males and often emerge during adolescence. As longitudinal studies in children are fraught with difficulties and limitations, animal models provide an invaluable tool to understand the mechanisms underlying the emergence and development of emotional dysregulation. Macaques provide an excellent model organism, as naturally occurring Social Subordination in Social groups is an ethologically valid chronic Social stress experience with reported pathological effects. Although this model has been used to investigate the effects of Social Subordination stress on numerous neural and behavioral outcomes in adults, few studies have focused on elucidating its effects during development. In this chapter, we review the effects of chronic Subordination stress in adult macaques, but also the emerging literature on its neurodevelopmental consequences, particularly for females. Findings indicate that Social Subordination affects brain structure and function, particularly corticolimbic circuits that regulate Social and emotional processes and endocrine function. This neural adaptation may enhance the ability of subordinates to effectively navigate Social environments requiring rapid recognition of Social signals and the Social status of conspecifics relative to self. This translational animal model of Social stress is vital to understand the basic mechanisms and principles that translate Social experiences into developmental outcomes in our own species.

  • Social Subordination stress and serotonin transporter polymorphisms associations with brain white matter tract integrity and behavior in juvenile female macaques
    Cerebral Cortex, 2014
    Co-Authors: Vasiliki Michopoulos, Jodi R Godfrey, Mar M Sanchez, Mark E Wilson, Brittany R Howell, David A Gutman, Xiaodong Zhang, Govind Nair
    Abstract:

    We examined the relationship between Social rank and brain white matter (WM) microstructure, and socioemotional behavior, and its modulation by serotonin (5HT) transporter (5HTT) polymorphisms in prepubertal female macaques. Using diffusion tensor imaging and tract-based spatial statistics, Social status differences were found in medial prefrontal cortex (mPFC) WM and cortico-thalamic tracts, with subordinates showing higher WM structural integrity (measured as fractional anisotropy, FA) than dominant animals. 5HTT genotype-related differences were detected in the posterior limb of the internal capsule, where s-variants had higher FA than l/l animals. Status by 5HTT interaction effects were found in (1) external capsule (middle longitudinal fasciculus), (2) parietal WM, and (3) short-range PFC tracts, with opposite effects in dominant and subordinate animals. In most regions showing FA differences, opposite differences were detected in radial diffusivity, but none in axial diffusivity, suggesting that differences in tract integrity likely involve differences in myelin. These findings highlight that differences in Social rank are associated with differences in WM structural integrity in juveniles, particularly in tracts connecting prefrontal, sensory processing, motor and association regions, sometimes modulated by 5HTT genotype. Differences in these tracts were associated with increased emotional reactivity in subordinates, particularly with higher submissive and fear behaviors.

  • crh receptor antagonism reverses the effect of Social Subordination upon central gabaa receptor binding in estradiol treated ovariectomized female rhesus monkeys
    Neuroscience, 2013
    Co-Authors: Vasiliki Michopoulos, Mar M Sanchez, Donna Toufexis, Molly Embree, Kathy Reding, John R Votaw, Ronald J Voll
    Abstract:

    Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social Subordination in Socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychoSocial stress of Subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using (18)F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to Socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of Social Subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.

Joaquin Sanz - One of the best experts on this subject based on the ideXlab platform.

  • Social history and exposure to pathogen signals modulate Social status effects on gene regulation in rhesus macaques
    Proceedings of the National Academy of Sciences of the United States of America, 2020
    Co-Authors: Joaquin Sanz, Paul L Maurizio, Noah Snydermackler, Noah D Simons, Tawni Voyles, Jordan N Kohn, Vasiliki Michopoulos, Mark L Wilson, Jenny Tung
    Abstract:

    Social experience is an important predictor of disease susceptibility and survival in humans and other Social mammals. Chronic Social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term Social status in female rhesus macaques to show that Social Subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to Social status at the time of sampling, but also to Social history (i.e., past Social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current Social status than those who climbed the Social hierarchy. Taken together, our results indicate that the effects of Social status on immune cell gene expression depend on pathogen exposure, pathogen type, and Social history-in support of Social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

  • Social history and exposure to pathogen signals modulate Social status effects on gene regulation in rhesus macaques
    bioRxiv, 2019
    Co-Authors: Joaquin Sanz, Paul L Maurizio, Noah Snydermackler, Noah D Simons, Tawni Voyles, Jordan N Kohn, Vasiliki Michopoulos, Mark L Wilson, Jenny Tung
    Abstract:

    Social experiences are an important predictor of disease susceptibility and survival in humans and other Social mammals. Chronic Social stress is thought to generate a pro-inflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term Social status in female rhesus macaques to show that Social Subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-kB-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-kB and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to Social status at the time of sampling, but also to Social history (i.e., past Social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current Social status than those who climbed the Social hierarchy. Together, our results indicate that the effects of Social status on immune cell gene expression depend on pathogen exposure, pathogen type, and Social history; in support of Social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

Donna Toufexis - One of the best experts on this subject based on the ideXlab platform.

  • Social Subordination alters estradiol induced changes in cortico limbic brain volumes in adult female rhesus monkeys
    Psychoneuroendocrinology, 2020
    Co-Authors: Katherine M Reding, Mar M Sanchez, Mark E Wilson, Donna Toufexis, Martin M Styner
    Abstract:

    Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17β-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of Social Subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of Social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic Social stress to modulate these effects on brain structure.

  • effects of Social Subordination and oestradiol on resting state amygdala functional connectivity in adult female rhesus monkeys
    Journal of Neuroendocrinology, 2020
    Co-Authors: Katherine M Reding, Mark E Wilson, Donna Toufexis, David Grayson, Oscar Mirandadominguez, Siddarth Ray, Damien A Fair, Mar M Sanchez
    Abstract:

    Preclinical studies demonstrate that chronic stress modulates the effects of oestradiol (E2) on behaviour through the modification of the amygdala and the medial prefrontal cortex (mPFC) neuronal structure. Clinical studies suggest that alterations in amygdala functional connectivity (FC) with the mPFC may be associated with stress-related phenotypes, including mood and anxiety disorders. Thus, identifying the effects of stress and E2 on amygdala-mPFC circuits is critical for understanding the neurobiology underpinning the vulnerability to stress-related disorders in women. In the present study, we used a well-validated rhesus monkey model of chronic psychoSocial stress (subordinate Social rank) to examine effects of E2 on subordinate (SUB) (i.e. high stress) and dominant (DOM) (i.e. low stress) female resting-state amygdala FC with the mPFC and with the whole-brain. In the non-E2 treatment control condition, SUB was associated with stronger left amygdala FC to subgenual cingulate (Brodmann area [BA] 25: BA25), a region implicated in several psychopathologies in people. In SUB females, E2 treatment strengthened right amygdala-BA25 FC, induced a net positive amygdala-visual cortex FC that was positively associated with frequency of submissive behaviours, and weakened positive amygdala-para/hippocampus FC. Our findings show that subordinate Social rank alters amygdala FC and the impact of E2 on amygdala FC with BA25 and with regions involved in visual processing and memory encoding.

  • crh receptor antagonism reverses the effect of Social Subordination upon central gabaa receptor binding in estradiol treated ovariectomized female rhesus monkeys
    Neuroscience, 2013
    Co-Authors: Vasiliki Michopoulos, Mar M Sanchez, Donna Toufexis, Molly Embree, Kathy Reding, John R Votaw, Ronald J Voll
    Abstract:

    Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social Subordination in Socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychoSocial stress of Subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using (18)F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to Socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of Social Subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.

  • Social Subordination impairs hypothalamic pituitary adrenal function in female rhesus monkeys
    Hormones and Behavior, 2012
    Co-Authors: Vasiliki Michopoulos, Katherine M Reding, Mark E Wilson, Donna Toufexis
    Abstract:

    Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) Social groups regardless of group size. As a consequence of their low Social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic-pituitary-adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether Social Subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that Social Subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute Social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following Social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychoSocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies.

  • Social Subordination produces distinct stress related phenotypes in female rhesus monkeys
    Psychoneuroendocrinology, 2012
    Co-Authors: Vasiliki Michopoulos, Donna Toufexis, Melinda Higgins, Mark E Wilson
    Abstract:

    Social Subordination in female macaques is imposed by harassment and the threat of aggression and produces reduced control over one's Social and physical environment and a dysregulation of the limbic-hypothalamic-pituitary-adrenal axis resembling that observed in people suffering from psychopathologies. These effects support the contention that this particular animal model is an ethologically relevant paradigm in which to investigate the etiology of stress-induced psychological illness related to women. Here, we sought to expand this model by performing a discriminate analysis (DA) on 33 variables within three domains; behavioral, metabolic/anthropomorphic, and neuroendocrine, collected from Socially housed female rhesus monkeys in order to assess whether exposure to Social Subordination produces a distinct phenotype. A receiver operating characteristic (ROC) curve was also calculated to determine each domain's classification accuracy. DA found significant markers within each domain that differentiated dominant and subordinate females. Subordinate females received more aggression, showed more submissive behavior, and received less of affiliation from others than did dominant females. Metabolic differences included increased leptin, and reduced adiponectin in dominant compared to subordinate females. Dominant females exhibited increased sensitivity to hormonal stimulation with higher serum LH in response to estradiol, cortisol in response to ACTH, and increased glucocorticoid negative feedback. Serum oxytocin, CSF DOPAC and serum PACAP were all significantly higher in dominant females. ROC curve analysis accurately predicted Social status in all three domains. Results suggest that Socially house rhesus monkeys represent a cogent animal model in which to study the physiology and behavioral consequences of chronic psychoSocial stress in humans.