Showing papers on "Corticosterone published in 2009"

Dynamic regulation of mitochondrial function by glucocorticoids

Abstract: Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function—mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity—were regulated by long-term corticosterone (CORT) treatment in an inverted “U”-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.

Stress Response and the Value of Reproduction: Are Birds Prudent Parents?

Abstract: In vertebrates, stressors such as starvation or predator attacks stimulate the rapid elevation of circulating glucocorticoid hormones, triggering physiological and behavioral responses that aid immediate survival but simultaneously inhibit reproduction. This stress response has been proposed to serve as a physiological mediator of life-history trade-offs: when the value of current reproduction is high relative to the value of future reproduction and survival, a mitigated stress response is expected to enable successful breeding and maximize fitness. Using phylogenetic comparative analyses, we investigated baseline and peak stress-induced plasma corticosterone levels during parental care in 64 bird species. We found that (1) species with a higher value of the current brood relative to future breeding mounted weaker corticosterone responses during acute stress, and (2) females in species with more female-biased parental care had weaker corticosterone responses. These results support the brood value hypothesis, suggesting that the stress response evolves as an adaptive basis for life-history strategies. Further, we found that (3) baseline corticosterone correlated positively with brood value and negatively with body mass, and (4) peak corticosterone was greater in species breeding at higher latitudes. The latter findings suggest that circulating corticosterone concentrations might be matched to the anticipated demands and risks during nesting.

Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory.

Abstract: Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN55,212-2 (5–50 ng per 0.2 μL per side), infused bilaterally into the BLA of male Sprague–Dawley rats immediately after inhibitory avoidance training, induced dose-dependent enhancement of 48-h retention. Conversely, the CB1 receptor antagonist AM251 (0.07–0.28 ng per 0.2 μL per side) administered after training into the BLA induced inhibitory avoidance retention impairment. Furthermore, intra-BLA infusions of a low and nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory enhancement induced by concurrent administration of WIN55,212-2. Delayed infusions of WIN55,212-2 or AM251 administered into the BLA 3 h after training or immediate posttraining infusions of these drugs into the adjacent central amygdala did not significantly alter retention performance. Last, intra-BLA infusions of a low and otherwise nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory-enhancing effect induced by systemic administration of corticosterone (3 mg/kg, s.c.). These findings indicate that endocannabinoids in the BLA enhance memory consolidation and suggest that CB1 activity within this brain region is required for enabling glucocorticoid effects on memory consolidation enhancement.

Regulation of hippocampal H3 histone methylation by acute and chronic stress

Abstract: The hippocampal formation is a brain region noted for its plasticity in response to stressful events and adrenal steroid hormones. Recent work has shown that chromatin remodeling in various brain regions, including the hippocampus, is associated with the effects of stress in a variety of models. We chose to examine the effects of stress, stress duration, corticosterone administration, and fluoxetine treatment on the levels of hippocampal histone H3 methylation at lysines 4, 9, and 27, marks associated, respectively, with active transcription, heterochromatin formation, and transcriptional repression. We found that acute stress increased the levels of H3K9 tri-methylation (H3K9me3) in the dentate gyrus (DG) and CA1, while it reduced levels of H3K9 mono-methylation (H3K9me1) and H3K27 tri-methylation (H3K27me3) in the same regions, and had no effect on levels of H3K4 tri-methylation (H3K4me3). Seven days of restraint stress reduced levels of H3K4me3 in the CA1 and H3K27me3 in the DG and CA1, while increasing basal levels of H3K9me3. Chronic restraint stress (CRS) for 21 days mildly increased levels of H3K4me3 and reduced H3K9me3 levels in the DG. Treatment with fluoxetine during CRS reversed the decrease in DG H3K9me3, but had no effect on the other marks. These results show a complex, surprisingly rapid, and regionally specific pattern of chromatin remodeling within hippocampus produced by stress and anti-depressant treatment that may open an avenue of understanding the interplay of stress and hippocampal gene expression, and reveal the outlines of a potential chromatin stress response that may be diminished or degraded by chronic stress.

Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats

Abstract: Several studies have supported the idea that ionotropic glutamate N-methyl-d-aspartate receptor (NMDA) is an important player in the etiology of psychopathologies, such as anxiety disorders and major depression. Additionally, studies have shown that ketamine induces antidepressant effects in humans as well as in rodents subjected to animal models of depression. In this context, the present study was aimed to evaluate behavioral and physiological effects of acute and chronic administration of ketamine, a NMDA receptor antagonist, in rats exposed to chronic mild stress (CMS). After 40 days of CMS, rats were treated with ketamine (15 mg/kg) and sweet food consumption, body and adrenal gland weight, corticosterone and adrenocorticotropic (ACTH) hormone levels, and hippocampal BDNF protein levels were assessed. Our findings demonstrated that CMS evoked anhedonia, induced hypertrophy of adrenal gland, impaired gain of body weight and increased corticosterone and ACTH circulating levels in rats. Acute and chronic treatment with ketamine reversed the increase in adrenal gland weight, promoted regain of body weight, and normalized corticosterone and ACTH circulating levels. Repeated, but not acute, administration of ketamine reversed anhedonia-like behavior, although the treatment with ketamine per se increased sweet food consumption in non-stressed rats. Finally, acute and chronic ketamine treatment did not alter hippocampal BDNF protein levels in stressed rats. In conclusion, these findings support the idea of a putative role of NMDA receptors in mood-related symptoms, and rapid and robust effects of ketamine in reverting mainly physiological alterations induced by chronic mild stressful situations in rats.

Stress, the hippocampus, and epilepsy

Abstract: Stress is among the most frequently self-reported precipitants of seizures in patients with epilepsy. This review considers how important stress mediators like corticotropin-releasing hormone, corticosteroids, and neurosteroids could contribute to this phenomenon. Cellular effects of stress mediators in the rodent hippocampus are highlighted. Overall, corticosterone--with other stress hormones--rapidly enhances CA1/CA3 hippocampal activity shortly after stress. At the same time, corticosterone starts gene-mediated events, which enhance calcium influx several hours later. This later effect serves to normalize activity but also imposes a risk for neuronal injury if and when neurons are concurrently strongly depolarized, for example, during epileptic activity. In the dentate gyrus, stress-induced elevations in corticosteroid level are less effective in changing membrane properties such as calcium influx; here, enhanced inhibitory tone mediated through neurosteroid effects on gamma-aminobutyric acid (GABA) receptors might dominate. Under conditions of repetitive stress (e.g., caused from experiencing repetitive and unpredictable seizures) and/or early life stress, hormonal influences on the inhibitory tone, however, are diminished; instead, enhanced calcium influx and increased excitation become more important. In agreement, perinatal stress and elevated steroid levels accelerate epileptogenesis and lower seizure threshold in various animal models for epilepsy. It will be interesting to examine how curtailing the effects of stress in adults, for example, by brief treatment with antiglucocorticoids, may be beneficial to the treatment of epilepsy.

Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats.

Abstract: Physical and psychological stressors not only enhance activity of the hypothalamo-pituitary-adrenocortical axis, but also cause oxidative damage by inducing an imbalance between the in vivo pro-oxidant and antioxidant status. The involvement of adrenal steroid stress hormones in oxidative damage associated with these stressors has not been extensively investigated. Therefore, this study was designed to probe any direct role of glucocorticoids on induction of oxidative processes by comparing the effects of low, intermediate and high doses of exogenously administered corticosterone, without other applied stressors, on a wide range of key components of the antioxidant defence system. The data presented here indicate a substantial decline in antioxidant defences by actions of corticosterone, evidenced by coordinate decreases in the activities in the brain, liver and heart of free-radical scavenging enzymes superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and glutathione reductase (GR), as well as the non-enzymatic antioxidants glutathione (GSH) and serum urate. Also, lipid peroxidation and protein carbonyl contents, oxidative stress markers, were found to be significantly increased in brain, liver and heart. The compromised in vivo antioxidant status was strikingly analogous to the deleterious effects of restraint stress, indicating a direct effect of stress hormones on induction of oxidative damage during physical or psychological stress. A dose-dependent decrease of SOD and CAT, and increase in protein oxidation was observed between the high (40 mg/kg) and low (10 mg/kg) doses of corticosterone. The findings have fundamental implications for oxidative stress as a major pathological mechanism in the maladaptation to chronic stress. Thus, the study suggests that stress hormones have a causal role in impacting oxidative processes induced during the adaptive response. This may hold important implications for pharmacological interventions targeting cellular antioxidants as a promising strategy for protecting against oxidative insults in various psychiatric and non-psychiatric conditions induced by physical or psychological stress.

Down‐Regulation of Hypothalamic Kisspeptin and its Receptor, Kiss1r, mRNA Expression is Associated with Stress‐Induced Suppression of Luteinising Hormone Secretion in the Female Rat

Abstract: Identification of kisspeptin (Kiss1) and its G protein-coupled receptor 54 (Kiss1r) as an essential component of the hypothalamic-pituitary-gonadal (HPG) axis controlling gonadotrophin secretion raises the possibility that kisspeptin-Kiss1r signalling may play a critical role in the transduction of stress-induced suppression of reproduction. We examined the effects of: (i) three different stressors, known to suppress pulsatile luteinising hormone (LH) secretion; (ii) corticotrophin-releasing factor (CRF); and (iii) corticosterone on Kiss1 and Kiss1r expression in key hypothalamic sites regulating gonadotrophin secretion: the medial preoptic area (mPOA) and arcuate nucleus (ARC). Ovariectomised oestrogen-replaced rats were implanted with i.v., subcutaneous or i.c.v. cannulae. Blood samples were collected at 5-min intervals for 5-6 h for detection of LH. Quantitative reverse transcriptase-polymerase chain reaction was used to determine Kiss1 and Kiss1r mRNA levels in brain punches of the mPOA and ARC collected 6 h after restraint, insulin-induced hypoglycaemia or lipopolysaccharide stress, or after i.c.v. administration of CRF, or acute or chronic subcutaneous administration of corticosterone. We observed down-regulation of at least one component of the kisspeptin-Kiss1r signalling system by each of the stress paradigms within the mPOA and ARC. CRF decreased Kiss1 and Kiss1r expression in both the mPOA and ARC. Both acute and chronic stress levels of corticosterone resulted in a concomitant decrease in Kiss1 and an increase in kiss1r mRNA expression in the mPOA and ARC. This differential regulation of Kiss1 and Kiss1r might account for the lack of effect corticosterone has on pulsatile LH secretion. Considering the pivotal role for kisspeptin-Kiss1r signalling in the control of the HPG axis, these results suggest that the reduced Kiss1-Kiss1r expression may be a contributing factor in stress-related suppression of LH secretion.

Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats

Abstract: Early life stress in humans can affect the development of neurons and neurotransmitter systems and predispose an individual to the subsequent development of depression. Similarly, in rats, maternal separation causes anxiety and depressive-like behavior and decreased corticosterone levels. Patients receiving pharmacological treatment for depression often experience negative side-effects or do not respond optimally and therefore the use of exercise as alternative antidepressant treatment is investigated. The aim of the study was to see whether rats subjected to both early life stress and chronic stress later in life show differences in depressive-like behavior, neurotrophin levels, stress hormone levels and antioxidant capacity of serum after chronic voluntary exercise as treatment. Rat pups were maternally separated and one group were allowed access to running wheels for 6 weeks while control rats were also handled and put in cages without running wheels. All rats were subjected to chronic restraint stress during adulthood. A forced swim test was done to test for depressive-like behavior. Neurotrophins were measured in the ventral hippocampus and striatum; baseline stress hormones were measured in blood plasma as well as the anti-oxidative potential of serum. Compared to controls, rats that exercised had no difference in baseline stress hormones, but had decreased immobility times in the forced swim test, increased brain derived neurotrophic factor (BDNF) levels in the striatum and decreased anti-oxidative potential of their serum. The mechanism by which depressive-like behavior was improved may have been mediated through increased striatal BDNF levels, resulting in increased neuroplasticity and the prevention of neuronal death.

Postnatal Stress in Birds: A Novel Model of Glucocorticoid Programming of the Hypothalamic-Pituitary-Adrenal Axis

Abstract: There is growing international interest in how environmental conditions experienced during development can shape adult phenotypes and the extent to which such induced changes are adaptive. One physiological system that links an individual to changes in environmental circumstances during development is the hypothalamic-pituitary-adrenal axis. Mammalian studies have linked early postnatal stress to later changes in the hypothalamic-pituitary-adrenal axis; however, the physiological link [lactational corticosterone (CORT) transfer] between mother and offspring during postnatal development constrains the ability to determine the direct effects of such stressors on subsequent physiology and behavior. Here we present a novel model using an avian species, the zebra finch (Taeniopygia guttata), in which maternal hormonal transfer during postnatal development is likely to be absent. Postnatal exposure of chicks to the stress hormone CORT was manipulated for a 16-d period up until nutritional independence (28 d), and the long-term effects on the physiological response to stress determined. CORT doses were scaled to mimic the physiological response of juvenile birds to a capture-handling-restraint protocol. CORT-fed birds showed exaggerated and prolonged responses to acute stress at 60 d of age. Our results clearly demonstrate that postnatal stress has significant long-term effects on the physiological stress response in birds and provides a potential mechanism underlying long-term behavioural responses to developmental conditions. This study represents the first direct evidence for postnatal glucocorticoid programming of the stress response using this novel model for postnatal stress. This model therefore provides an important tool with which to investigate the role of glucocorticoids in shaping adult phenotypes.

Increased Phospholipase A2 Activity and Inflammatory Response But Decreased Nerve Growth Factor Expression in the Olfactory Bulbectomized Rat Model of Depression: Effects of Chronic Ethyl-Eicosapentaenoate Treatment

Abstract: An increased inflammatory response and deficient synthesis of neurotrophic factors (NTFs) may contribute to the etiology of depression. However, the interrelationship between inflammation and NTFs is unknown. Recently, ethyl-eicosapentaenoate (EPA) has been used to treat depression. The mechanism by which EPA benefits depression is also unclear. Using the olfactory bulbectomized (OB) rat model of depression, this study evaluated two pathways from bulbectomy to the induction of depression-like changes (the inflammation–hypothalamic–pituitary–adrenal axis–stress response pathway and inflammation–nerve growth factor–memory pathway) and the effect of EPA on these pathways. When compared with sham-operated rats fed a control diet, significantly increased locomotor and rearing activities in an “open field,” impaired memory in the Morris water maze, increased expression of corticotrophin-releasing factor (CRF), and increased secretion of corticosterone were found in OB rats. mRNA expression of nerve growth factor (NGF) was significantly lower in the hippocampus, and phospholipase A2 (PLA2) was higher in the hypothalamus; this change was associated with increased interleukin-1β (IL-1β) and prostaglandin E2 (PGE2) in the serum and brain. EPA treatments normalized these behavioral impairments and reduced CRF expression and corticosterone secretion. EPA also reduced serum concentrations of IL-1β and PGE2, but reversed NGF reduction. Similar to the effects of EPA, the anti-inflammatory drug celecoxib significantly reduced blood PGE2, IL-1β, and corticosterone concentrations and increased NGF expression in OB rats. Furthermore, anti-NGF treatment blocked EPA effects on behavior. These results suggest that an interaction exists between inflammation and NGF in the depression model. EPA may improve depression via its anti-inflammation properties and the upregulation of NGF.

11β-Hydroxysteroid Dehydrogenase Type 1 and Its Role in the Hypothalamus-Pituitary-Adrenal Axis, Metabolic Syndrome, and Inflammation

Abstract: Context: 11β-Hydroxysteroid dehydrogenase (11β-HSD) enzymes are now appreciated to be important regulators of hormone action at a tissue level. 11β-HSD1 is widely expressed and increases glucocorticoid action through its unique ability to convert inactive glucocorticoids (cortisone in man, 11-dehydrocorticosterone in rodents) to their active forms (cortisol and corticosterone, respectively). The enzyme has roles in the normal hypothalamus-pituitary-adrenal (HPA) axis, has been implicated in metabolic syndrome, and may modulate various aspects of the immune response. Evidence Acquisition: A review of published, peer-reviewed medical literature (1990 to June 2009) on the physiology and pathophysiology of 11β-HSD1 was performed with an emphasis on HPA axis consequences, the metabolic syndrome, and the inflammatory response. Evidence Synthesis: Studies of patients with genetic defects in 11β-HSD1 action show abnormal HPA axis responses with hyperandrogenism being a major consequence. The mechanisms underlying...

How does corticosterone affect parental behaviour and reproductive success? A study of prolactin in black-legged kittiwakes

Abstract: Summary 1. An emergency life-history stage is expressed in breeding vertebrates when the immediate survival is threatened by poor energetic conditions (i.e. allostatic overload). This emergency life-history stage shifts energy investment away from reproduction and redirects it toward immediate survival. 2. In birds, this emergency life-history stage is promoted by a release of the stress hormone corticosterone. However, how corticosterone reduces the expression of parental cares remains to be clarified. One hypothesis is that the release of corticosterone may also affect prolactin levels, a pituitary hormone widely involved in regulating parental behaviours. 3. We tested this hypothesis by experimentally increasing corticosterone levels of chick-rearing black-legged kittiwakes ( Rissa tridactyla ) over a 2-day period and by monitoring prolactin levels over an 8-day period. We also investigated whether this hormonal manipulation affected nest attendance, the motivation to come back to the nest after a short-term stress and breeding success. 4. Corticosterone treatment resulted in a significant increase in plasma corticosterone levels during the first 2 days, which returned to pre-treatment values at day 3. This short-term corticosterone increase was accompanied by a 30% decrease in prolactin levels. Prolactin levels were reduced in a progressive and persistent manner and did not return to their initial levels when corticosterone levels returned to pre-treatment levels. Moreover, although corticosterone levels had returned to pre-treatment values, low prolactin levels were associated with a reduced nest attendance and a greater latency to come back to the nest after a short-term stress. This hormonal treatment also significantly reduced breeding success. 5. This experimental treatment strongly supports the idea that the secretion of these two hormones might be mechanistically linked. Thus, we showed that even a relatively short-term increase in corticosterone levels can durably affect plasma prolactin levels. Therefore, the well-established suppressive action of corticosterone on parental behaviour is probably mediated and reinforced through an effect on prolactin levels. This study highlights the need to consider the potential synergistic effects of these two hormones when studying on the hormonal basis of parental decisions.

Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease caused by genetic and non-genetic factors. Most AD cases may be triggered and promoted by non-genetic environmental factors. Clinical studies have reported that patients with AD show enhanced baseline levels of stress hormones in the blood, but their physiological significance with respect to the pathophysiology of AD is not clearly understood. Here we report that AD mouse models exposed to restraints for 2 h daily on 16 consecutive days show increased levels of beta-amyloid (Abeta) plaque deposition and commensurable enhancements in Abeta(1-42), tau hyperphosphorylation, and neuritic atrophy of cortical neurons. Repeated restraints in Tg2576 mice markedly increased metabolic oxidative stress and down-regulated the expression of MMP-2, a potent Abeta-degrading enzyme, in the brain. These stress effects were reversed by blocking the activation of the hypothalamus-pituitary-adrenal gland axis with the corticotropin-releasing factor receptor antagonist NBI 27914, further suggesting that over-activation of the hypothalamic-pituitary-adrenal axis is required for stress-enhanced AD-like pathogenesis. Consistent with these findings, corticosteroid treatments to cultured primary cortical neurons increased metabolic oxidative stress and down-regulated MMP-2 expression, and MMP-2 down-regulation was reversed by inhibition of oxidative stress. These results suggest that behavioral stress aggravates AD pathology via generation of metabolic oxidative stress and MMP-2 down-regulation.

Behavioural and neurochemical consequences of early weaning in rodents.

Abstract: Among all mammalian species, pups are highly dependent on their mother not only for nutrition, but also for physical interaction. Therefore, disruption of the mother-pup interaction changes the physiology and behaviour of pups. We review how maternal separation in the early developmental period brings about changes in the behaviour and neuronal systems of the offspring of rats and mice. Early weaning in mice results in adulthood a persistent increase in anxiety-like and aggressive behaviour. The early-weaned mice also show higher hypothalamic-pituitary-adrenal activity in response to novelty stress. Neurochemically, the early-weaned male mice, but not female mice, show precocious myelination in the amygdala, decreased brain-derived neurotrophic factor protein levels in the hippocampus and prefrontal cortex, and reduced bromodeoxyuridine immunoreactivity in the dentate gyrus. Because higher corticosterone levels are persistently observed up to 48 h when the mice are weaned on postnatal day 14, the exposure of the developing brain to higher corticosterone levels may be one of the effects of early weaning. These results suggest that deprivation of the mother-infant interaction during the late lactating period results in behavioural and neurochemical changes in adulthood and that these stress responses are sexually dimorphic (i.e. the male is more vulnerable to early weaning stress).

Corticosterone alters AMPAR mobility and facilitates bidirectional synaptic plasticity.

Abstract: Background: The stress hormone corticosterone has the ability both to enhance and suppress synaptic plasticity and learning and memory processes. However, until today there is very little known about the molecular mechanism that underlies the bidirectional effects of stress and corticosteroid hormones on synaptic efficacy and learning and memory processes. In this study we investigate the relationship between corticosterone and AMPA receptors which play a critical role in activity-dependent plasticity and hippocampal-dependent learning. Methodology/Principal Findings: Using immunocytochemistry and live cell imaging techniques we show that corticosterone selectively increases surface expression of the AMPAR subunit GluR2 in primary hippocampal cultures via a glucocorticoid receptor and protein synthesis dependent mechanism. In agreement, we report that corticosterone also dramatically increases the fraction of surface expressed GluR2 that undergo lateral diffusion. Furthermore, our data indicate that corticosterone facilitates NMDAR-invoked endocytosis of both synaptic and extra-synaptic GluR2 under conditions that weaken synaptic transmission. Conclusion/Significance: Our results reveal that corticosterone increases mobile GluR2 containing AMPARs. The enhanced lateral diffusion properties can both facilitate the recruitment of AMPARs but under appropriate conditions facilitate the loss of synaptic AMPARs (LTD). These actions may underlie both the facilitating and suppressive effects of corticosteroid hormones on synaptic plasticity and learning and memory and suggest that these hormones accentuate synaptic efficacy.

Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11β-hydroxysteroid dehydrogenase type 2

Abstract: Prenatal stress (PS) produces persistent abnormalities in anxiety-related behaviors, stress responsivity, susceptibility to psychopathology and hippocampal changes in adult offspring. The hippocampus shows a remarkable degree of structural plasticity, notably in response to stress and glucocorticoids. We hypothesized that PS would differentially affect hippocampal neurogenesis in rats selectively bred for genetic differences in anxiety-related behaviors and stress responsivity. Pregnant dams of high anxiety-related behavior (HAB) and low anxiety-related behavior (LAB) strains were stressed between days 5 and 20 of pregnancy. The survival of newly generated hippocampal cells was found to be significantly lower in 43-day-old HAB than in LAB male offspring of unstressed pregnancies. PS further reduced newly generated cell numbers only in HAB rats, and this was paralleled by a reduction in doublecortin-positive cell numbers, indicative of reduced neurogenesis. As maternal plasma corticosterone levels during PS were similar in both strains, we examined placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of maternal corticosterone to inert 11-dehydrocorticosterone and thus serves as a physiological 'barrier' to maternal glucocorticoids. PS significantly increased placental 11β-HSD2 activity in LAB, but not HAB, rats. We conclude that PS differentially affects the number of surviving newly generated cells and neurogenesis in HAB and LAB rats. The high sensitivity of hippocampal neurogenesis to PS in HAB rats is paralleled by a failure to increase placental 11β-HSD2 activity after stress rather than by different maternal corticosterone responses. Hence, stress-induced placental 11β-HSD2 expression may be critical in protecting the fetal brain from maternal stress-induced effects on adult neurogenesis.

Gene expression changes in the hypothalamus provide evidence for regionally-selective changes in IL-1 and microglial markers after acute stress.

Abstract: Recent work from our laboratory and others has shown that certain stressors increase expression of the pro-inflammatory cytokine interleukin-1β (IL-1) in the hypothalamus. The first goal of the following studies was to assess the impact of acute stress on other key inflammatory factors, including both cytokines and cell surface markers for immune-derived cells resident to the CNS in adult male Sprague Dawley rats exposed to intermittent footshock (80 shocks, 90 s variable ITI, 5 s each). While scattered changes in IL-6 and GFAP were observed in the hippocampus and cortex, we found the hypothalamus to be exquisitely sensitive to the effects of footshock. At the level of the hypothalamus, mRNA for IL-1 and CD14 were significantly increased, while at the same time CD200R mRNA was significantly decreased. A subsequent experiment demonstrated that propranolol (20 mg/kg i.p.) blocked the increase in IL-1 and CD14 mRNA observed in the hypothalamus, while the decrease in CD200R was unaffected by propranolol. Interestingly, inhibition of glucocorticoid synthesis via injection of metyrapone (50 mg/kg s.c.) plus aminoglutethimide (100 mg/kg s.c.) increased basal IL-1 mRNA and augmented IL-1 and CD14 expression provoked by footshock. Injection of minocycline, a putative microglial inhibitor, blocked the IL-1 response to footshock, while CD14 and CD200R were unaffected. Together, these gene expression changes (i) provide compelling evidence that stress may provoke neuroinflammatory changes that extend well beyond isolated changes in a single cytokine; (ii) suggest opposing roles for classic stress-responsive factors (norepinephrine and corticosterone) in the modulation of stress-related neuroinflammation; (iii) indicate microglia within the hypothalamus may be key players in stress-related neuroinflammation; and (iv) provide a potential mechanism (increased CD14) by which acute stress primes reactivity to later immune challenge.

Peripheral tumors induce depressive-like behaviors and cytokine production and alter hypothalamic-pituitary-adrenal axis regulation.

Abstract: A strong and positive correlation exists between chronic disease and affective disorders, but the biological mechanisms underlying this relationship are not known. Here we show that rats with mammary cancer exhibit depression- and anxiety-like behaviors in the absence of overt sickness behaviors. The production of proinflammatory cytokines, known to induce depressive-like behaviors, was elevated in the periphery and in the hippocampus of rats with tumors compared with controls. In tumor-bearing rats, circulating corticosterone, which inhibits cytokine signaling, was suppressed following a stressor, and gene expression of hippocampal glucocorticoid receptors was elevated. The results establish that tumors alone are sufficient to trigger changes in emotional behaviors. Dampened glucocorticoid responses to stressors may exacerbate the deleterious effects of tumor-induced cytokines on affective states.

Exogenous and endogenous corticosterone alter feather quality

Abstract: We investigated how exogenous and endogenous glucocorticoids affect feather replacement in European starlings (Sturnus vulgaris) after approximately 56% of flight feathers were removed. We hypothesized that corticosterone would retard feather regrowth and decrease feather quality. After feather regrowth began, birds were treated with exogenous corticosterone or sham implants, or endogenous corticosterone by applying psychological or physical (food restriction) stressors. Exogenous corticosterone had no impact on feather length and vane area, but rectrices were lighter than controls. Exogenous corticosterone also decreased inter-barb distance for all feathers and increased barbule number for secondaries and rectrices. Although exogenous corticosterone had no affect on rachis tensile strength and stiffness, barbicel hooking strength was reduced. Finally, exogenous corticosterone did not alter the ability of Bacillus licheniformis to degrade feathers or affect the number of feathers that failed to regrow. In contrast, endogenous corticosterone via food restriction resulted in greater inter-barb distances in primaries and secondaries, and acute and chronic stress resulted in greater inter-barb distances in rectrices. Food-restricted birds had significantly fewer barbules in primaries than chronic stress birds and weaker feathers compared to controls. We conclude that, although exogenous and endogenous corticosterone had slightly different effects, some flight feathers grown in the presence of high circulating corticosterone are lighter, potentially weaker, and with altered feather micro-structure.

Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain.

Abstract: Chronic stress and impaired glucocorticoid receptor (GR) feedback are important factors for the compromised hypothalamic-pituitary-adrenal (HPA) axis activity. We investigated the effects of chronic 21 day isolation of Wistar rats on the extrinsic negative feedback part of HPA axis: hippocampus (HIPPO) and prefrontal cortex (PFC). In addition to serum corticosterone (CORT), we followed GR subcellular localization, GR phosphorylation at serine 232 and serine 246, expression of GR regulated genes: GR, CRF and brain-derived neurotropic factor (BDNF), and activity of c-Jun N-terminal kinase (JNK) and Cdk5 kinases that phosphorylate GR. These parameters were also determined in animals subjected to acute 30 min immobilization, which was taken as 'normal' adaptive response to stress. In isolated animals, we found decreased CORT, whereas in animals exposed to acute immobilization, CORT was markedly increased. Even though the GR was predominantly localized in the nucleus of HIPPO and PFC in acute, but not in chronic stress, the expression of GR, CRF, and BDNF genes was similarly regulated under both acute and chronic stresses. Thus, the transcriptional activity of GR under chronic isolation did not seem to be exclusively dependent on high serum CORT levels nor on the subcellular location of the GR protein. Rather, it resulted from the increased Cdk5 activation and phosphorylation of the nuclear GR at serine 232 and the decreased JNK activity reflected in decreased phosphorylation of the nuclear GR at serine 246. Our study suggests that this nuclear isoform of hippocampal and cortical GR may be related to hypocorticism i.e. HPA axis hypoactivity under chronic isolation stress.

Differential corticosteroid modulation of inhibitory synaptic currents in the dorsal and ventral hippocampus.

Abstract: Corticosterone has been known to mediate the effects of stress on cognitive functions associated with the hippocampus. Acting at mineralocorticosteroid receptors (MRs) and glucocorticosteroid receptors (GRs), corticosterone exerts several effects in the hippocampus and elsewhere. Assuming that there are major functional differences between the dorsal hippocampus (DH) and ventral hippocampus (VH), and that these may be regulated by local interneurons, we analyzed the action of corticosterone on inhibitory synaptic currents in patch-clamped pyramidal neurons, recorded in acute slices of DH and VH. Corticosterone, through activation of MRs, reduced the frequency of spontaneous IPSCs in VH but not in DH neurons, and markedly suppressed paired-pulse facilitation of evoked inhibitory synaptic currents. These effects were mimicked by aldosterone, an MR agonist, and were blocked by an MR antagonist. In contrast, corticosterone caused an increase in the magnitude of IPSCs in both the DH and VH via its activation of GRs. This effect was mimicked by a GR agonist, dexamethasone, which produced a slow-onset, large potentiation reaching a peak within 45-60 min after onset of perfusion, and was blocked by a GR antagonist. The amplitude of mIPSCs was markedly increased by the GR agonist, indicating a synaptic locus of effect. These results indicate that corticosterone has a dual action, which may underlie the differential functional effects of stress hormones in the DH and VH.