The Stress Hormone Corticosterone Increases Synaptic ��-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors via Serum- and Glucocorticoid-inducible Kinase (SGK) Regulation of the GDI-Rab4 Complex

Corticosterone, the major stress hormone, plays an important role in regulating neuronal functions of the limbic system, although the cellular targets and molecular mechanisms of corticosteroid signaling are largely unknown. Here we show that a short treatment of corticosterone significantly increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission and AMPAR membrane trafficking in pyramidal neurons of prefrontal cortex, a key region involved in cognition and emotion. This enhancing effect of corticosterone is through a mechanism dependent on Rab4, the small GTPase-controlling receptor recycling between early endosome and plasma membrane. Guanosine nucleotide dissociation inhibitor (GDI), which regulates the cycle of Rab proteins between membrane and cytosol, forms an increased complex with Rab4 after corticosterone treatment. Corticosterone also triggers an increased GDI phosphorylation at Ser-213 by the serum- and glucocorticoid-inducible kinase (SGK). Moreover, AMPAR synaptic currents and surface expression and their regulation by corticosterone are altered by mutating Ser-213 on GDI. These results suggest that corticosterone, via SGK phosphorylation of GDI at Ser-213, increases the formation of GDI-Rab4 complex, facilitating the functional cycle of Rab4 and Rab4-mediated recycling of AMPARs to the synaptic membrane. It provides a potential mechanism underlying the role of corticosteroid stress hormone in up-regulating excitatory synaptic efficacy in cortical neurons.     

Arginine metabolic pathways determine its therapeutic benefit in experimental heatstroke: Role of Th1/Th2 cytokine balance

We have demonstrated that therapeutic administration of L-arginine (L-arg) (120 mg/kg) at +2 h of whole body hyperthermia (WBH) could rescue the mice from heatstroke-induced death. Studies were undertaken to elucidate the role of L-arg in the immunomodulation of the heat-stressed mice. Administration of L-arginine (L-arg), (120 mg/kg, i.p.), at +2 h of WBH, rescued the mice from heat-induced death and reduced the hypothermia. At +4 and +24 h of WBH, levels of IL-1beta, IFN-gamma, nitrite, TNF-alpha, IL-4, TGF-beta1, inducible form of nitric oxide synthase (iNOS), and corticosterone significantly increased compared to the sham group. The elevated levels of Th(1) cytokines, namely TNF-alpha, IL-1beta, IFN-gamma, nitrite, and iNOS, decreased significantly both at +4 and +24 h of WBH, following L-arg administration. However, L-arg administration did not reduce the increased levels of Th(2) cytokines, namely IL-4 and TGF-beta1, in WBH mice at +4 h of WBH. L-arg administration significantly increased the levels of Th(2) cytokines at +24 h of WBH, compared to the saline-treated WBH mice. L-arg administration significantly increased both the splenic and hepatic arginase activity at +4 and +24 h of WBH compared to the saline-treated WBH mice. L-NAME treatment at +2 h of WBH and anti-TGF-beta antibody treatment at 0 h of WBH significantly increased the mortality compared to the saline-treated WBH mice. Altered liver histopathology was attenuated following the administration of L-arg at +2 h of WBH. These results suggest that therapeutic administration of L-arg at appropriate concentration and time attenuates the acute inflammatory response, leading to the rescue of mice from heatstroke.     

Corticosterone shifts reproductive behaviour towards self-maintenance in the barn owl and is linked to melanin-based coloration in females

Trade-offs between the benefits of current reproduction and the costs to future reproduction and survival are widely recognized. However, such trade-offs might only be detected when resources become limited to the point where investment in one activity jeopardizes investment in others. The resolution of the trade-off between reproduction and self-maintenance is mediated by hormones such as glucocorticoids which direct behaviour and physiology towards self-maintenance under stressful situations. We investigated this trade-off in male and female barn owls in relation to the degree of heritable melanin-based coloration, a trait that reflects the ability to cope with various sources of stress in nestlings. We increased circulating corticosterone in breeding adults by implanting a corticosterone-releasing-pellet, using birds implanted with a placebo-pellet as controls. In males, elevated corticosterone reduced the activity (i.e. reduced home-range size and distance covered within the home-range) independently of coloration, while we could not detect any effect on hunting efficiency. The effect of experimentally elevated corticosterone on female behaviour was correlated with their melanin-based coloration. Corticosterone (cort-) induced an increase in brooding behaviour in small-spotted females, while this hormone had no detectable effect in large-spotted females. Cort-females with small eumelanic spots showed the normal body-mass loss during the early nestling period, while large spotted cort-females did not lose body mass. This indicates that corticosterone induced a shift towards self-maintenance in males independently on their plumage, whereas in females this shift was observed only in large-spotted females.     

Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels

"The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre + post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups."     

围栏条件下母体密度应激对根田鼠 F1代性器官指数的影响

为探讨自然条件下母体密度应激对根田鼠F1代性器官指数的影响,通过在围栏内建立不同密度的母体种群获得相应的F1代个体,以此建立了不同密度的子代种群,并测定了母体种群建群者的血浆皮质酮含量,将建立子代种群后剩余的F1代个体带回实验室饲养.实验结束后,测定了全部F1代个体的性器官指数及皮质酮含量.结果表明,高密度母体种群建群者的皮质酮含量显著高于低密度母体种群建群者;出生于高密度母体种群的F1代个体处于高密度子代种群,其性器官指数显著低于出生于低密度母体种群且处于低密度子代种群的F1代个体,而皮质酮含量显著高于后者;出生于高密度母体种群的F1代个体处于低密度子代种群,其性器官指数及皮质酮含量与出生于低密度母体种群且处于低密度子代种群的F1代个体间无显著差异.此外,实验室饲养条件下,出生于高密度和低密度母体种群的F1代个体间的睾丸指数无显著差异.本研究结果说明,在根田鼠种群中,单一的母体密度应激对子代的性器官指数无影响,但生前应激子代在性成熟后,当再次遭遇密度应激时,其性器官指数显著降低,母体密度应激和当前环境对种群的未来繁殖能力具有耦合效应.     

北极的春季:迁徙鸟类抵达的生物学

一旦鸟类抵达北极区,迁徙鸟类必须调整其生理和行为以适应不可预知的雪盖、天气、食物资源和天敌胁迫。换言之,他们必须抵抗环境干扰(压力)以便尽早迁徙到苔原上的巢区并建立领域。然后,一旦外界环境有利时,它们就立即开始繁殖。这些鸟类的繁殖有一部分是利用低雪盖区域的微生境以及雪融较快的苔原斑块(特别是在柳树Salix sp．附近)。在北极地区,地面温度在日照若干小时后急剧上升,同时无脊椎动物开始活动。风速在地面柳枝和生草丛苔原10cm下几乎减弱为零。这些条件结合在一起提供了理想的避难所,对于早春迁徙到此的雀形目鸟类尤其如此。然而,如果环境调节变得更为恶劣,这些鸟类会离开。因为与南方越冬地相比,春季北极区条件具有潜在的严酷性,所以鸟类对于应激时的肾上腺皮质反应有所调整。雄鸟到达北极地区时对于剧烈应激刺激下的肾上腺酮的分泌有所提高,并且伴随着对于负反馈敏感性的下降和肾上腺皮质层细胞对于促肾上腺皮质激素作用反应的变化。同时,肾上腺酮结合蛋白(CBG)的水平也有所提高,以至于肾上腺酮的作用在恶劣的环境条件下得到缓冲。基因组受体水平的调节,尤其是在脑和肝脏中糖皮质类固醇类似受体与肾上腺酮的低亲合性,以及肾上腺酮的非基因组水平的作用,可能是很重要的。换言之,与抵达生物学有关的激素一行为系统是高度可变的[动物学报50(6)：948-960,2004]。     

单配制啮齿动物Pair Bond形成的神经调节机制

单配制啮齿动物社会结构的神经生物学原理可以通过实验室研究Social bonding而获得。在本文中,我们探讨了如何利用单配制的草原田鼠(Microtus ochrogaster)作为研究模型揭示pair bond形成的神经调控机制。我们进而探讨了单配制与多配制田鼠之间神经解剖学的差异以及神经化学物质的调节是怎样影响pair bond的。本篇综述还讨论了与pair bond形成有关的神经化学系统之间的相互影响以及pair bond形成过程中的两性差异。最后,我们预测了这一研究领域的未来研究方向以及研究social bonding的神经调控对人类健康的重要性。     

Combined effects of molt and chronic stress on heart rate, heart rate variability, and glucocorticoid physiology in European Starlings

Molt is an important life-history stage in avian species, but little is known about the effects of chronic stress during this period. Three weeks after the onset of molt, captive European starlings (Sturnus vulgaris) were exposed to 18 days of chronic stress, induced with four 30-minute randomized stressors presented daily. Birds showed no chronic-stress-induced changes in heart rate or heart rate variability when measured either during the middle of the day or at night. These data suggest that chronic stress did not alter the balance between sympathetic and parasympathetic nervous system regulation of cardiovascular function, which contrasts with data from an earlier study indicating that chronic stress profoundly alters cardiovascular function in non-molting starlings. Additionally, there was a significant increase in restraint-induced corticosterone secretion the first week of chronic stress that subsequently returned to pre-chronic-stress levels by the second week of exposure. The attenuated corticosterone response again contrasts with data from non-molting starlings that showed significant decreases in corticosterone responses. Consequently, the resistance to cardiovascular and corticosterone changes indicates that the physiological changes induced by chronic stress are greatly attenuated in molting birds. Overall, the data suggest that molt requires a degree of physiological stability that must be protected, so that if a bird is exposed to chronic stress during this life-history stage, molt takes priority.     

Neonatal hyperleptinaemia programmes anxiety-like and novelty seeking behaviours but not memory/learning in adult rats

Leptin treatment during lactation programmes for leptin resistance at adulthood, evidenced by hyperleptinaemia, hyperphagia and overweight. Since leptin is known to affect stress response, emotional behaviour and memory/learning performance, the objective of the present study was to evaluate whether neonatal hyperleptinaemia programmes anxiety-like and novelty-seeking behaviours as well as memory/learning in adult male rats. During the first 10 days of lactation (from PN1 to PN10), pups were s.c. injected once per day with either 50 μL of saline (SAL) or murine leptin (LEP — 8 μg/100 g of body mass, saline diluted). Serum leptin was assessed at PN10 and at PN150. Two separate experiments were carried out: 1) experiment one: at PN137, 29 SAL and 30 LEP rats were tested in the elevated plus-maze (EPM) and, at PN142, their behaviour was assessed in the hole board (HB) arena; 2) experiment two: at PN140, a different group of rats consisting of 53 SAL and 56 LEP animals were tested in the radial arm water maze (RAWM). Serum leptin concentration was higher in the LEP group at PN10 and at PN150. LEP animals spent significantly less time in the open arms of the EPM. Furthermore, the number of nose-pokes in the HB arena was higher in LEP rats. There were no differences between groups regarding latency to find the hidden platform in the RAWM. Our results suggests that a central mechanism of leptin resistance at adulthood, caused by neonatal hyperleptinaemia, is associated with an increased level of anxiety and also that it intensifies novelty seeking-behaviour.     

Peony Glycosides Protect Against Corticosterone-Induced Neurotoxicity in PC12 Cells

Preclinical and clinical investigations have shown the involvement of dysregulation of hypothalamic–pituitary–adrenal (HPA) axis in the pathogenesis of depression. Hypercortisolemia and the associated hippocampal atrophy were observed in patients with depression, which could be ameliorated by the treatment with antidepressants. Therefore, neuroprotection has been proposed to be one of the acting mechanisms of antidepressant. Previous studies in our laboratory have demonstrated the antidepressant-like activity of total glycosides of peony (TGP) in mice. This study aimed to examine the effect of TGP treatment on corticosterone-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Treating the cells with corticosterone at 200 μM for 48 h caused apoptotic cell death. The cytotoxicity was associated with the activation of caspase-3 activity and the decrease in the mRNA ratio of bcl-2 to bax. TPG treatment at increasing doses (1–10 mg/l) protected against the corticosterone-induced toxicity in PC12 cells in a dose-dependent manner. The cytoprotection afforded by TGP treatment was associated with the inhibition of caspase-3 activity and the up-regulation of bcl-2/bax mRNA ratio. The anti-apoptotic effect of TGP is therefore likely mediated by the suppression of the mitochondrial pathway leading to apoptosis.