Abstract:Exposure to stressors such as foot shock (FS) leads to increased expression of multiple inflammatory factors, including the proinflammatory cytokine interleukin-1 (IL-1) in the brain. Studies have indicated that there are sex differences in stress reactivity, suggesting that the fluctuations in gonadal steroid levels across the estrous cycle may play a regulatory role in the stress-induced cytokine expression. The present studies were designed to investigate the role of 17-β-estradiol (E2) and proge… Show more
“…First, steady-state levels of neuroinflammation appear to escalate in response to distinct stress challenges. Importantly, the nature of the neuroimmune response evoked by stress depends on key features of the individual, including genetic differences (sex and other genomic differences) and/or hormonal status of the subject (Arakawa et al , 2014, Duma et al , 2010, Hodes et al , 2014). Experiential factors, such as social experiences, appear to be particularly important drivers of neuroimmune differences across a wide range of species.…”
Section: Discussionmentioning
confidence: 99%
“…For instance, activation of the HPA axis does not lead to the sole release of GC hormone from the adrenal gland, but instead leads to the release of a multitude of other hormonal mediators, many of which have immunomodulatory properties (Deak, 2008). Notably, progesterone is a precursor steroid that is enzymatically and rapidly converted to corticosterone in the adrenal glands, and yet plasma progesterone evinces a rapid surge that parallels plasma corticosterone in both male (Hueston and Deak, 2014) and female (Arakawa et al , 2014) rats. Additionally, there are virtually no manipulations that adequately discriminate between corticosterone and progesterone action since metyrapone administration or ADX ablate both corticosterone and progesterone (Hueston and Deak, 2014), and most GC-selective antagonists do not adequately discriminate between corticosteroid and progestin receptors (Etgen and Barfield, 1986, Rupprecht et al , 1993).…”
Section: Neuroimmune Consequences Of Stress and Implications For Elabmentioning
confidence: 99%
“…Although very few studies have addressed sex differences in neuroimmune responses to stress, our lab recently completed a series of studies showing that ovariectomy led to (i) increased basal and stress-evoked expression of IL-1 in the PVN relative to sham-operated females, and that (ii) this effect was recovered by replacement of estradiol (Arakawa et al , 2014). Although we also observed some fluctuation in stress-dependent expression of IL-1 across the ovarian cycle (i.e., the IL-1 response in the PVN was less pronounced during metestrus), this latter effect requires additional follow-up studies to better understand the mechanism.…”
Section: Neuroimmune Consequences Of Stress and Implications For Elabmentioning
The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative, or antagonistic interactions between steroid hormone receptors (Estrogen and Glucocorticoid receptors); (iii) adverse social experiences incurred through repeated social defeat engage a dynamic process of immune cell migration from the bone marrow to brain and prime neuroimmune function; and (iv) early developmental exposure to an inflammatory stimulus (carageenin injection into the hindpaw) has a lasting influence on stress reactivity across the lifespan. As such, the present review provides a theoretical framework for understanding the role that neuroimmune mechanisms might play in stress plasticity and pathological outcomes, while at the same time pointing toward features of the individual (sex, developmental experience, stress history) that might ultimately be used for the development of personalized strategies for therapeutic intervention in stress-related pathologies.
“…First, steady-state levels of neuroinflammation appear to escalate in response to distinct stress challenges. Importantly, the nature of the neuroimmune response evoked by stress depends on key features of the individual, including genetic differences (sex and other genomic differences) and/or hormonal status of the subject (Arakawa et al , 2014, Duma et al , 2010, Hodes et al , 2014). Experiential factors, such as social experiences, appear to be particularly important drivers of neuroimmune differences across a wide range of species.…”
Section: Discussionmentioning
confidence: 99%
“…For instance, activation of the HPA axis does not lead to the sole release of GC hormone from the adrenal gland, but instead leads to the release of a multitude of other hormonal mediators, many of which have immunomodulatory properties (Deak, 2008). Notably, progesterone is a precursor steroid that is enzymatically and rapidly converted to corticosterone in the adrenal glands, and yet plasma progesterone evinces a rapid surge that parallels plasma corticosterone in both male (Hueston and Deak, 2014) and female (Arakawa et al , 2014) rats. Additionally, there are virtually no manipulations that adequately discriminate between corticosterone and progesterone action since metyrapone administration or ADX ablate both corticosterone and progesterone (Hueston and Deak, 2014), and most GC-selective antagonists do not adequately discriminate between corticosteroid and progestin receptors (Etgen and Barfield, 1986, Rupprecht et al , 1993).…”
Section: Neuroimmune Consequences Of Stress and Implications For Elabmentioning
confidence: 99%
“…Although very few studies have addressed sex differences in neuroimmune responses to stress, our lab recently completed a series of studies showing that ovariectomy led to (i) increased basal and stress-evoked expression of IL-1 in the PVN relative to sham-operated females, and that (ii) this effect was recovered by replacement of estradiol (Arakawa et al , 2014). Although we also observed some fluctuation in stress-dependent expression of IL-1 across the ovarian cycle (i.e., the IL-1 response in the PVN was less pronounced during metestrus), this latter effect requires additional follow-up studies to better understand the mechanism.…”
Section: Neuroimmune Consequences Of Stress and Implications For Elabmentioning
The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative, or antagonistic interactions between steroid hormone receptors (Estrogen and Glucocorticoid receptors); (iii) adverse social experiences incurred through repeated social defeat engage a dynamic process of immune cell migration from the bone marrow to brain and prime neuroimmune function; and (iv) early developmental exposure to an inflammatory stimulus (carageenin injection into the hindpaw) has a lasting influence on stress reactivity across the lifespan. As such, the present review provides a theoretical framework for understanding the role that neuroimmune mechanisms might play in stress plasticity and pathological outcomes, while at the same time pointing toward features of the individual (sex, developmental experience, stress history) that might ultimately be used for the development of personalized strategies for therapeutic intervention in stress-related pathologies.
“…162, 163, 164 Under conditions of severe and chronic stressor exposure however, not only does the HPA axis remain activated, but a neuroinflammatory milieu ensues within many brain structures including the hypothalamus and hippocampus. 165, 166, 167, 168, 169, 170, 171, 172 …”
Section: Factors That May Contribute To Stress-induced Alternations Imentioning
Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect on cognition may provide insight into why adolescence may be a vital period for correct conditioning of future hippocampal function.
“…It can be noted, however, that females display a robust increase in IL-1β expression after footshock, an effect that varies significantly in response to ovarian hormones. 50 Although CORT habituation to restraint has been shown to occur similarly in males and females, 51 habituation to other stressors, such as the presently-used forced swim, remains to be examined and may proceed differently between the sexes.…”
Section: Experiments 3 Examined How a History Of Restraint Would Modifymentioning
A wide range of stress-related pathologies such as post-traumatic stress disorder are thought to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic-pituitary-adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to ten days of restraint alone (60 min daily), forced swim alone (30 min daily), or daily sequential exposure to restraint (60 min) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim to sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC), and hippocampus (HPC). Sequential exposure to restraint and swim increased IL-1β in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL-6 and TNF-α responses in the HPC and PFC, respectively, that did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL-1β response evoked by swim exposure imposed immediately after the 6th day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL-1β response after swim in comparison to acutely-exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds (a) independent of HPA axis habituation; (b) likely requires more daily sessions of stress to develop; and that (c) IL-1β displays a greater tendency to habituate after repeated stress challenges than other stress-reactive cytokines.
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