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Classical signs of chronic stress after 14 days of repeated restraint in cannulated animals (n=18-22). (A) The body weight gain was smaller in repeatedly restrained animals. (B) During 24 h of starvation the body weight decrease was not influenced by previous chronic stress. (C) The relative weight of adrenal glands was higher in stressed animals. (D) There was a tendency for reduced relative thymus weight in 14R animals (p=0.09). (E) The resting corticosterone levels were higher after 12R, but the cannulation abolished this difference. *p<0.05, **p<0.01 vs. control, non-stressed animals; 14R – 14 days repeated restraint daily for 60 min
Source publication
Objective:
In the everyday life, stress is deemed as something unfavorable that may enhance the risk for the development or worsen a disease. However, in its nature, stress is adaptive reaction of the body. Its main characteristic is the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Previously, we have shown that activation o...
Citations
... Many research studies have linked permanent stressful conditions with chronic diseases, such as cardiovascular diseases, high blood pressure, diabetes, chronic obstructive pulmonary diseases, immunological disorders, and even cancer. The combination of chronic diseases, ageing, and stress is considered as among the most dangerous health risk factors, especially for populations inhabiting modern, metropolitan cities [9,10]. ...
... The body weight gain is typically decreased after application of chronic stressors not only in rats [32,33], but also in mice [34,35]. Thus, it was important to confirm that repeated interventions do not keep the animals in a constant stressed state. ...
Preclinical studies on rodents should follow the 3R principle minimising the suffering of the animals. To do so, some researchers use inhalation anaesthetic induction even before intraperitoneal injection. However, several studies suggested that both interventions might influence the behaviour of the animals. We aimed to test whether intraperitoneal injection alone or in combination with isoflurane anaesthesia is a preferable treatment method 30 min before a social test. Male C57BL/6 mice were studied using a behavioural test battery comparing three groups (one control group and intraperitoneal saline-treated groups with or without short isoflurane inhalation). Our results confirmed that both interventions had no profound influence on the conventionally measured parameters of social tests (interest in sociability, social discrimination memory, social interaction as well as resident–intruder test) and were not acutely stressful (measured by similar ACTH levels between the groups) not even after repeated administration (similar body weight gain during the one-week observation period). Taking into consideration the possible long-term harmful effect of isoflurane inhalation, we recommend using intraperitoneal injection without it as saline injection did not violate the 3R principle inducing only mild stress.
... All mice receiving RS showed a significant lack in body weight gain (Figure 2-figure supplement 2, Figure 6-figure supplement 1, Figure 7-figure supplement 2), confirming that these mice were stressed, because a decrease in body weight gain is generally accepted as reflecting stress. (Jeong et al., 2013;Filaretova et al., 2013;Sántha et al., 2015). Nevertheless, changes in body weight were not affected by manipulation of crus I PCs (Figure 2-figure supplement 2) or VTA-projecting DCN neurons upon CNO administration ( Figure 6-figure supplement 1, Figure 7-figure supplement 2). ...
Although cerebellar alterations have been implicated in stress symptoms, the exact contribution of the cerebellum to stress symptoms remains to be elucidated. Here, we demonstrated the crucial role of cerebellar neurons projecting to the ventral tegmental area (VTA) in the development of chronic stress-induced behavioral alterations in mice. Chronic chemogenetic activation of inhibitory Purkinje cells in crus I suppressed c-Fos expression in the DN and an increase in immobility in the tail suspension test or forced swimming test, which were triggered by chronic stress application. The combination of adeno-associated virus-based circuit mapping and electrophysiological recording identified network connections from crus I to the VTA via the dentate nucleus (DN) of the deep cerebellar nuclei. Furthermore, chronic inhibition of specific neurons in the DN that project to the VTA prevented stressed mice from showing such depression-like behavior, whereas chronic activation of these neurons alone triggered behavioral changes that were comparable with the depression-like behaviors triggered by chronic stress application. Our results indicate that the VTA-projecting cerebellar neurons proactively regulate the development of depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders in human.
... In many experiments where stress-induced hypertension was observed, special rat strains prone to hypertension were used (Mansi and Drolet 1997;McDougall et al. 2000;Cui et al. 2003) or additional treatments (salt, chronic hypoxia, etc.) were employed which facilitated an increase in BP (Porter and King 2009;Ma et al. 2008). Otherwise, acute or chronic restraint stress may not induce significant hypertension (Filaretova et al. 2013;Carda et al. 2015). The model we used involved multiple exposures to predator scent; therefore, the stress was prolonged and severe. ...
Posttraumatic stress disorder (PTSD) is associated with myocardial injury, but changes in coronary regulatory mechanisms in PTSD have not been investigated. This study evaluated the effect of PTSD-inducing stress on coronary tone and its regulation by nitric oxide (NO) and voltage-gated K⁺ channels. PTSD was induced by exposing rats to predator stress, 15 min daily for 10 days, followed by 14 stress-free days. Presence of PTSD was confirmed by the elevated plus-maze test. Coronary tone was evaluated from changes in coronary perfusion pressure of Langendorff isolated hearts. Predator stress induced significant decreases in coronary tone of isolated hearts and in blood pressure of intact rats. L-NAME, a non-selective NO synthase (NOS) inhibitor, but not S-MT, a selective iNOS inhibitor, and increased coronary tone of control rats. In PTSD rats, both L-NAME and S-MT increased coronary tone. Therefore, the stress-induced coronary vasodilation resulted from NO overproduction by both iNOS and eNOS. NOS induction was apparently due to systemic inflammation as evidenced by increased serum interleukin-1β and C-reactive protein in PTSD rats. Decreased corticosterone in PTSD rats may have contributed to inflammation and its effect on coronary tone. PTSD was also associated with voltage-gated K⁺ channel dysfunction, which would have also reduced coronary tone.
... Following baseline sensory assessment, half of the rats in each sex group (16 males and 16 females) were exposed to RS for a period of 14 days (experimental days 19 to 33) for 2 hours a day. 48,49 Following 7 and 14 days of restraint (experimental days 26 and 33, respectively), behavioral testing was performed, and IFN-γ levels were measured. These measures were all on naïve rats that had not yet undergone any type of surgical intervention. ...
... To induce chronic stress, animals were restrained in the laboratory for a period of 2 hours once daily for 14 consecutive days between 9:00 am and 12:00 pm. 48,49 Restraint was carried out by placing the male and female rats (in separate batches) into a Perspex restraining enclosure comprised of four compartments, each 6 cm wide × 7 cm high × 18 cm long. 49 The partitions between animals were opaque. ...
Aims:
To investigate the effects and interactions of sex and stress (provoked by chronic restraint [RS]) on pain-like behavior in a rat model of trigeminal neuropathic pain.
Methods:
The effects of sex and RS (carried out for 14 days as a model for stress) on somatosensory measures (reaction to pinprick, von Frey threshold) in a rat model of trigeminal neuropathic pain were examined. The study design was 2 × 4, with surgery (pain) and sham surgery (no pain) interacting with male restrained (RS) and unrestrained (nRS) rats and female RS and nRS rats. A total of 64 Sprague Dawley rats (32 males and 32 females) were used. Half of the animals in each sex group underwent RS, and the remaining half were left unstressed. Following the RS period, trigeminal neuropathic pain was induced by unilateral infraorbital nerve chronic constriction injury (IOCCI). Half of the animals in the RS group and half in the nRS group (both males and females) were exposed to IOCCI, and the remaining halves to sham surgery. Elevated plus maze (EPM) assessment and plasma interferon gamma (IFN-γ) levels were used to measure the effects of RS. Analysis of variance (ANOVA) was used to assess the effects of stress, sex, and their interactions on plasma IFN-γ levels, changes in body weight, EPM parameters, tactile allodynia, and mechanohyperalgesia. Pairwise comparisons were performed by using Tukey post hoc test corrected for multiple comparisons.
Results:
Both male and female RS rats showed significantly altered exploratory behavior (as measured by EPM) and had significantly lower plasma IFN-γ levels than nRS rats. Rats exposed to RS gained weight significantly slower than the nRS rats, irrespective of sex. Following RS but before surgery, RS rats showed significant bilateral reductions in von Frey thresholds and significantly increased pinprick response difference scores compared to nRS rats, irrespective of sex. From 17 days postsurgery, RSIOCCI rats showed significantly reduced von Frey thresholds and significantly increased pinprick response difference scores compared to nRS-IOCCI rats, and the von Frey thresholds were significantly lower in females than in males. RS-sham females-but not RS-sham males-developed persistently reduced thresholds and increased pinprick response difference scores.
Conclusion:
RS produced an increased bilateral sensitivity to stimuli applied to the vibrissal pad following infraorbital nerve injury, irrespective of sex. This observed sensitivity subsequently persisted in RS-sham female rats but not in RS-sham male rats. Stress induced a significant but moderate increase in pain-like behavior in female rats compared to male rats. RS had no significant sex effects on IFN-γ levels, EPM parameters, or body weight gain. This suggests that stress may have a selective effect on pain-like behavior in both sexes, but the possible mechanisms are unclear.
... The gastroprotective action of glucocorticoids during stress may be related with their beneficial effect on the gastric blood flow. Blood supply is a critical component of gastroprotection and gastric injury [51]. The cardiovasular parameters, including blood pressure are the main determinants of the blood supply, and are in direct relationship with the development of ulceration [52]. ...
Background
The brain and the gut interact bi-directionally through the brain-gut axis. The interaction is mediated by the autonomic nervous system and the hypothalamic-pituitary-adrenocortical (HPA) system. The first brilliant demonstration of the brain-gut interactions was the cephalic phase of gastric and pancreatic secretion discovered by Ivan Pavlov, the first physiologist who was awarded the Nobel Prize for Physiology or Medicine in 1904. This review aims to identify the HPA system as a key hormonal branch of the brain-gut axis in stress.
Methods
We first outlined main components of the brain-gut axis and then focused on the HPA system as a key hormonal branch of the brain-gut axis in stress. We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question.
Results
Seventy-one articles were included in the review, the eleventh of them were articles of Filaretova L. and co-authors. We will discuss in our articles how an endocrinological approach to gastroenterological field can advance our understanding of the HPA axis role in regulation of gastric mucosal integrity and uncover new findings. According to these findings activation of the HPA system is gastroprotective component of the brain-gut axis in stress but not ulcerogenic one as it was generally accepted. Corticotropin-releasing factor (CRF) and glucocorticoids are important natural players provided gastroprotection. The results suggest that an initial action of endogenous glucocorticoids, including stress- and CRF-produced ones, as well as exogenous glucocorticoids, even used at pharmacological doses, is physiological gastroprotective. Prolongation of the hormonal action may lead to the transformation of gastroprotective hormonal effect to proulcerogenic one.
Conclusion
The findings of this review demonstrate that corticotropin-releasing factor and glucocorticoids contribute to the realization of the brain-gut interactions and that activation of the HPA system is gastroprotective component of this interaction in stress.
... There was a significant lack of gain in body weight in response to 21 days of restraint stress (92.4%; p < 0.05) compared to the unstressed pair-fed control rats (Figure 1). The significant decrease in body weight gain is a pathophysiological indicator of stress and a stress parameter generally accepted in the literature (Chiba et al., 2012;Sántha et al., 2012;Filaretova et al., 2013). ...
Stress is well-known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognized in the development of neurodegenerative disorders, such as Alzheimer's disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3, and 21 days) were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occluding, and glucose transporter-1) and astroglia (GFAP). Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, 1-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5, and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes, cognitive and behavioral dysfunctions.
... Additionally, neonatal stress disrupts serotonergic functioning throughout brain regions including the prefrontal cortex (Arbourelius and Eklund, 2007;Xue et al., 2013). Combined with elevated corticosterone levels (Dias et al., 2014;Filaretova et al., 2013), these neural markers can be used as molecular indicators of stress or anxiety when evaluating the benefits of early-life interventions such as EE. ...
