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The neuronal membrane glycoprotein M6a (GPM6A) belongs to the family of myelin proteolipid protein and plays a role in neuronal remodeling and plasticity. Decreased expression of GPM6A mRNA is observed in the hippocampal tissue of suicide victims who suffered from depression and after chronic stress exposure in animals. The regulatory mechanisms that impact expression of GPM6A under chronic stress or in pathological conditions are not well understood. Previously, miRNAs miR‐133b, miR‐124‐3p, and miR‐9‐5p have been shown to regulate the expression of Gpm6a mRNA under normal conditions. Here, we employed the paradigm of chronic‐restraint stress in rats and using quantitative polymerase chain reaction (qPCR) showed down‐regulation of expression of Gpm6a and the brain‐derived neurotrophic factor (Bdnf) genes at mRNA level as well as miR‐133b, and miR‐124‐3p, but not miR‐9‐5p in the hippocampus of chronically stressed rats. Furthermore, we observed alterations in the expression of histone deacetylase (Hdac5) and myocyte enhancer factor 2C (Mef2c) mRNAs. Our data suggest that chronic stress influences Gpm6a expression by miR‐124‐mediated impact on the expression of Hdac5 and Mef2c. Upon miR‐124 over‐expression in hippocampal neurons cultured in vitro, we observed enhanced neuronal arborization as evaluated by Sholl analysis, increased Gpm6a and Mef2c expression, and decreased Hdac5 expression. Moreover, treatment of hippocampal neurons cultured in vitro with BDNF resulted in an elevation in the miR‐124‐3p expression, a decrease in the miR‐9‐5p expression but did not affect miR‐133b. This was accompanied by augmented expression of Gpm6a and Mef2c mRNAs and significantly lower levels of Hdac5 mRNA. Altogether, these results indicate that the regulatory mechanism that influence expression of Gpm6a under chronic stress involves miR‐124‐mediated impact on the expression of Hdac5 and Mef2c and a role of BDNF in the activation of Gpm6a expression. [ABSTRACT FROM AUTHOR]

An abundance of knowledge has been collected describing the involvement of neuroendocrine parameters in major depression. The hypothalamic–pituitary–adrenocortical (HPA) axis regulating cortisol release has been extensively studied; however, attempts to target the HPA axis pharmacologically to treat major depression have failed. This review focuses on the importance of the adrenocortical stress hormone aldosterone, which is released by adrenocorticotropic hormone and angiotensin, and the mineralocorticoid receptor (MR) in depression. Depressed patients, in particular those with atypical depression, have signs of central hyperactivation of the aldosterone sensitive MR, potentially as a consequence of a reactive aldosterone release induced by low blood pressure and as a result of low sensitivity of peripheral MR. This is reflected in reduced heart rate variability, increased salt appetite and sleep changes in this group of patients. In addition, enlarged brain ventricles, compressed corpus callosum and changes of the choroid plexus are associated with increased aldosterone (in relation to cortisol). Furthermore, subjects with these features often show obesity. These characteristics are related to a worse antidepressant treatment outcome. Alterations in choroid plexus function as a consequence of increased aldosterone levels, autonomic dysregulation, metabolic changes and/or inflammation may be involved. The characterization of this regulatory system is in its early days but may identify new targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

There is still a lack of consistent evidence on dysregulation of steroid stress hormones cortisol and aldosterone in premenstrual syndrome (PMS). We aimed to test the hypothesis that, in healthy women, salivary aldosterone concentrations are higher in those with PMS compared to controls, particularly during the luteal phase of the menstrual cycle. In total, 99 female subjects (49 women with and 50 women without PMS) participated in a prospective non‐interventional case–control study. Saliva sampling was performed in the follicular (day 8), early luteal (day 20) and late luteal phase (2 days before expected onset of bleeding) of the menstrual cycle in the morning and the evening. The results confirmed the hypothesis that salivary aldosterone concentrations are higher in women with PMS during the early luteal phase compared to controls (p <.01) in the evening. Early luteal phase aldosterone concentrations positively correlated with the frequency of premenstrual symptoms. Women with PMS exhibited a flatter morning to evening aldosterone slope compared to controls (p <.05). Morning and evening salivary cortisol concentrations were unchanged throughout the menstrual cycle in both groups of women. In conclusion, evening salivary aldosterone, but not cortisol concentrations, are increased in women with PMS during the early luteal phase compared to controls. Cortisol does not appear to be involved in the mechanisms contributing to the course of PMS. High evening salivary aldosterone in the early luteal phase may represent an important risk factor and could be of predictive value for the occurrence of premenstrual symptoms. [ABSTRACT FROM AUTHOR]

Background: Simultaneous evaluation of barrier protein expression in the gut and the brain and their modulation under stress conditions have not been studied before now. As the permeability and function of the gut and blood‐brain barrier are different and both express the MRs, we hypothesized that stress of post‐weaning social isolation induces changes in tight junction protein expression in the gut which are (1) independent of changes in the brain and (2) are mediated via the mineralocorticoid receptor (MR). Methods: First, using UPLC‐MS/MS we have successfully validated and selected a dose (1.2 mg/rat/day) of the MR antagonist spironolactone to treat female rats exposed to stress of chronic isolation or control conditions from postnatal day 21 for 9 weeks. Key Results: Isolation stress caused an enhancement of gene expression of occludin and ZO‐1 and a decrease in claudin‐5 and MR expression in both the small intestine and prefrontal cortex. Isolation stress failed to decrease claudin‐5 (small intestine) and MR (prefrontal cortex) gene expression in spironolactone‐treated rats. MR blockade resulted in a decrease in claudin‐15 expression in the small intestine. Anxiogenic effect of chronic stress, measured in elevated plus‐maze test, was partly prevented by spironolactone treatment. Conclusions & Inferences: Claudins, the main regulators of intestinal barrier permeability responded to chronic stress of social isolation and/or simultaneous blockade of MR in female rats by alterations independent of changes in the brain cortex. The results suggest a physiological role of MR in the control of claudin expression in the small intestine, but not in the brain cortex. [ABSTRACT FROM AUTHOR]

The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood-brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. Even if intuitively the BSCB could be considered as the morphological extension of the BBB into the spinal cord, evidence suggests that this is not so. The BSCB shares the same principal building blocks with the BBB; nevertheless, it seems that morphological and functional differences may exist between them. Dysfunction of the BSCB plays a fundamental role in the etiology or progression of several pathological conditions of the spinal cord, such as spinal cord injury, amyotrophic lateral sclerosis, and radiation-induced myelopathy. This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the BSCB, and the potential role of BSCB dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BSCB. Ann Neurol 2011; [ABSTRACT FROM AUTHOR]

Background and Purpose: Treatment with thiazolidinediones, insulin-sensitizing drugs, enhances adipogenesis, which may result in unwanted increase in adiposity. Based on the suggested metabolic effects of oxytocin, the aims of the present study were to: (i) determine whether chronic treatment with oxytocin exerts positive effects on white adipose tissue growth without increasing adiposity; (ii) investigate possible mechanisms of action of oxytocin by measuring the level of gene expression of adipogenic factors; and (iii) test the hypothesis that oxytocin's effect on adipose tissue involves specific activation of eukaryotic elongation factor 2 (eEF2).Experimental Approach: Adult rats were subcutaneously treated with oxytocin (3.6 µg·100 g⁻¹ body weight day⁻¹) via osmotic minipumps for 2 weeks. Adipocytes from epididymal adipose tissue were isolated and their size evaluated by light microscopy. Gene expression of adipogenic and angiogenic factors was determined by real-time PCR and dephosphorylation of eEF2 by immunoblotting.Key Results: Oxytocin treatment decreased the diameter of adipocytes and increased the epididymal adipose tissue protein content without changing the adipose tissue mass. Increases in fatty acid binding protein, peroxisome proliferator-activated receptor γ, insulin-sensitive glucose transporter 4, leptin and CD31 mRNA levels were noted in the epididymal and/or retroperitoneal fat tissue of oxytocin-treated rats. Oxytocin enhanced the dephosphorylation of eEF2 in the epididymal adipose tissue.Conclusions and Implications: The present results demonstrate that subchronic treatment with oxytocin induces adipogenic and angiogenic effects and that the eEF2 signalling pathway is involved in these effects of oxytocin on adipose tissue in vivo. These findings are likely to motivate further research and indicate new approaches for modulating adipose tissue morphology and metabolism. [ABSTRACT FROM AUTHOR]

Glucocorticoids and other steroids produced in the adrenal cortex are altered in chronic stress situations associated with enhanced anxiety. A useful tool to evaluate changes in adrenal steroids during stress and anxiety under both laboratory and real-life stress situations is determination of steroids in saliva. The main advantages of this technique are its noninvasiveness and its measurement of biologically active free hormone levels. Salivary cortisol is a valuable indicator of the activity of the hypothalamic-pituitary-adrenocortical axis, which is known to be altered in psychiatric disorders. Measurements of salivary cortisol helped to reveal changes that would otherwise remained undetected, such as increase in cortisol release in spontaneously occurring panic attacks. By selecting only the subjects with high and low trait anxiety, we have brought evidence confirmed by others that high trait anxiety may be associated with an inability to respond with adequate cortisol release during stress. Papers on the relationship between salivary dehydroepiandrosterone and trait anxiety or anxiety disorders are rare, and this stress hormone deserves more attention. Almost nothing is known on aldosterone and anxiety. We have modified the methodology of aldosterone radioimmunoassay by concentrating the saliva and validated it biologically by demonstrating daily variation and gender differences. We have provided the first data on the relationship between aldosterone and trait anxiety. Obtained results show a significant negative correlation between morning salivary aldosterone concentrations and trait anxiety scores in women (luteal phase), but not in men. A more proper elucidation of the association between aldosterone and anxiety seems to be an important target of further research. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the influence of trait anxiety and menstrual cycle phase on neuroendocrine activation during combined mental and physical stress procedure in 40 healthy female subjects. Women at the upper (anxious) and lower (nonanxious) limits of the normal range of a trait anxiety scale were exposed to the stress procedure consisting of a mental component (Stroop test) and handgrip exercise. Salivary cortisol levels, cardiovascular parameters, and cognitive performance in the Stroop test were evaluated. Stress-induced cortisol levels and the rise in systolic blood pressure were affected by both trait anxiety and menstrual cycle phase. The stress model used induced a significant cortisol elevation only in anxious women in the follicular phase. This group of women also exhibited greater increases in systolic blood pressure in response to handgrip exercise as compared to anxious ones in the luteal phase and to nonanxious women in either phase. In nonanxious women, stress-induced cortisol levels positively correlated with cognitive performance. In contrast, a negative correlation trend was observed in anxious subjects. Thus, in subjects with low but not high trait anxiety, enhanced cortisol concentrations seem to be associated with better cognitive performance. The results suggest that women with high trait anxiety exhibit greater cardiovascular and hormonal sensitivity to stress stimuli during the follicular phase. [ABSTRACT FROM AUTHOR]

This study aimed to contribute to the knowledge of cardiovascular regulation associated with repeated exercise by evaluating untraditional parameters in the model of voluntary wheel running. Possible changes in cardiac phenylethanolamine N-methyltransferase (PNMT) gene expression were evaluated using running for 3 weeks in four rat strains, and the hypothesis that voluntary wheel running modifies mean arterial pressure (MAP) responses to oxytocin administration was verified. Running activity increased gradually and was high in spontaneously hypertensive rats (SHR) and Sprague-Dawley rats, while low in Wistar rats. The levels of PNMT mRNA in the left but not right atrium increased significantly in rat strains exhibiting high physical activity. Concentrations of PNMT mRNA were significantly higher in SHR and Sprague-Dawley compared to those in Wistar rats, which ran much shorter distances. MAP was found to be higher in rats exposed to voluntary running, which might be the result of the cessation of the exercise 24 h before the measurements. Oxytocin treatment (5 μg/kg and 30 μg/kg i.v.) resulted in significant increase in MAP in both control and running animals in a dose-dependent manner. In conclusion, voluntary wheel running failed to modify sensitivity to cardiovascular action of oxytocin but resulted in increased gene expression of PNMT in left, but not right, heart atrium in a running activity–dependent manner. [ABSTRACT FROM AUTHOR]

Housing of animals in an enriched environment (EE) has many positive effects on brain structure and function and can facilitate recovery from various brain injuries. The purpose of this study was to evaluate whether enriched rearing could alter the stress response induced by repeated immune challenge and to investigate the influence of EE and immune challenge on glutamate receptor gene expression in the hippocampus. Male 2-mo-old Wistar rats were kept under standard conditions (SC) or in an EE for 5 weeks. Immune challenge was performed by Escherichia coli lipopolysaccharide (LPS) injected repeatedly (ip) in increasing doses (10, 20, and 40 μg/kg/mL) once daily for five consecutive days. The animals were decapitated 2 h after the last injection. Blood samples, adrenals, and hippocampi were collected. LPS induced an increase in plasma and adrenal levels of corticosterone and a transient decrease in body weight of animals kept under SC, but not in an EE. Enriched housing resulted in an increase in adrenal weights and enhanced gene expression of hippocampal AMPA GluR1 receptor subunit. Concerning the LPS treatment, no effects on adrenal and thymus weights and glutamate receptor mRNA levels in the hippocampus were noticed. Thus, vulnerability to some negative effects of repeated immune challenge may be modified by environmental conditions associated with changes in brain plasticity. The fact that differences in housing conditions change stress response has to be considered in biomedical research. [ABSTRACT FROM AUTHOR]

It is known that the development and plasticity of the neuroendocrine system can be affected by many factors, and that adverse events during the prenatal period can result in long-lasting changes in adulthood. This study was aimed at evaluating the possible consequences for offspring from chronic inflammation during pregnancy. Chronic inflammation was simulated by treatment with increasing doses of lipopolysaccharide (LPS) to dams on days 15 through 19 of pregnancy. Attempts were made to prevent possible negative alterations by keeping animals in an enriched environment (EE). Maternal exposure to LPS resulted in a significant reduction of body weight of male offspring during the weaning period. This difference remained until the age of 63 days in controls (C), but not in animals reared in EE. The content of dopamine in the nucleus accumbens was found to be lower in prenatally stressed (PS) adult males. Furthermore, prenatal exposure to maternal immune challenge was associated with lower locomotor activity in elevated plus maze and increased number of skips in the beam-walking test, as observed in female offspring. No differences in ACTH and corticosterone concentrations with regard to prenatal treatment were found; however, both groups kept in EE showed increased levels of corticosterone as well as enlarged adrenal glands. Thus, immune activation during pregnancy may induce long-term changes in brain catecholamines and behavior, but it is not harmful to basal hormone secretion in the offspring. [ABSTRACT FROM AUTHOR]

In our previous study, repeated stress in the neonatal period was found to slow habituation in the open field in adult rats. The objective of the present study was to investigate how chronic stress can affect habituation processes in the open field when occurring in adulthood. Animals were exposed to 1 week of immobilization on metal boards followed by 1 week of hypokinesis. After the stress procedure, rats were tested in the open field (once daily in 6-min sessions for four consecutive days). Immediately after the last open-field test, animals were decapitated. The rapidity of between- and within-session habituation was lower than in control rats. However, this lowering failed to be statistically significant compared with control rats. On the other hand, time latency to step down from an elevated platform was significantly increased in stress-exposed animals. Four days after the last stressful event, corticotropinreleasing hormone mRNA levels in the paraventricular nucleus were significantly increased, indicating a long-term activation of the hypothalamic-pituitaryadrenocortical axis. The results suggest that, in contrast to neonatal stress exposure, chronic emotional stress in adult rats does not represent a risk factor for the alteration of habituation processes. [ABSTRACT FROM AUTHOR]

Activation of the sympathoadrenal system, evaluated by plasmalevels of epinephrine (E) and norepinephrine (NE) after exposure of rats to variousstressors, is well documented. However, response of rats exposed longtermto a homotypic stressor and then exposed once to a heterotypic novelstressor is poorly understood. In the present study, we examined changes inplasma levels of catecholamines (CA) and corticosterone (COR) of rats after asingle (2-h) or long-term repeated immobilization (41 times, 2 h daily) and inrats adapted to long-term immobilization exposed once to the novel stress ofcold exposure or insulin or 2-deoxy-D-glucose (2DG) administration. Longtermimmobilization produced a significant elevation of basal plasma COR butnot NE and E levels. Long-term immobilized rats exposed to insulin or 2DGshowed significant elevation of plasma CA and COR levels in comparison to theadministration to control rats. Exposure of long-term immobilized and controlrats to cold stress increased plasma NE and COR, whereas plasma E was notsignificantly changed. The exposure of long-term immobilized rats to a furthersingle immobilization (2 h) increased plasma CA levels, but, in naive controlrats, the single immobilization produced more pronounced increases. Thesedata suggest that rats exposed to homotypic long-term immobilization are ableto respond to heterotypic stressors by higher activation of the sympathoadrenalsystem as compared with the control, previously unstressed rats. Reduced plasmaCA levels in long-term immobilized rats exposed to homotypic stressor aremost probably due to an adaptation at the level of brain regulatory centers. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II) type-1 (AT1) receptors are present in areas of the brain controlling autonomic nervous activity and the hypothalamic-pituitary-adrenal (HPA) axis, including CRH cells in the hypothalamic paraventricular nucleus (PVN). To determine whether brain AT1 receptors are involved in the activation of the HPA axis and sympathetic system during stress, we studied the effects of acute immobilization stress on plasma catecholamines, ACTH and corticosterone, and mRNA levels of CRH and CRH receptors (CRH-R) in the PVN in rats under central AT1 receptor blockade by the selective antagonist, Losartan. While basal levels of epinephrine, norepinephrine and dopamine in plasma were unaffected 30 min after icv injection of Losartan (10 μg), the increases after 5 and 20 min stress were blunted in Losartan treated rats (P<0.05 for norepinephrine, and P<0.01 for epinephrine and dopamine, vs controls). Basal or stress-stimulated plasma ACTH and corticosterone levels were unaffected by icv Losartan treatment. Using in situ hybridization studies, basal levels of CRH mRNA and CRH-R mRNA in the PVN were unchanged after icv Losartan. While Losartan had no effect on the increases in CRH-R mRNA levels 2 or 3 h after 1 h immobilization, it prevented the increases in CRH mRNA. The blunted plasma catecholamine responses after central AT1 receptor blockade indicate that endogenous Ang II in the brain is required for sympathoadrenal activation during immobilization stress. While Ang II appears not to be involved in the acute secretory response of the HPA axis, it may play a role in regulating CRH expression in the PVN. [ABSTRACT FROM AUTHOR]