Days Of Stress Exposure Research Articles

Tinnitus Generation and Behavioral Changes Caused by Chronic Stress: A Behavioral and Brain Study in a Rat Model.

This study explores the connection between chronic stress and tinnitus, a phantom auditory perception, using an animal model. Rats were subjected to 2 h of daily restraint stress for 10 days. Tinnitus was assessed on the last day of stress exposure using the gap response of pre-pulse inhibition acoustic reflex, measured at 60 dB background sound level at 8, 16, and 20 kHz. Chronic stress-exposed rats were categorized into two groups: tinnitus (RTG) and non-tinnitus (RNTG). Various tests, including hearing assessments (distortion product otoacoustic emissions and auditory brainstem response), behavioral evaluations (elevated plus maze test and forced swimming test), and immunohistochemical studies in the auditory and limbic brain regions, were conducted to understand the relationship between chronic stress, tinnitus, and behavioral changes. Following chronic restraint stress, 64.3% of the rats exhibited tinnitus with no audiometric changes. EPM and FST indicated an increase of anxiety- and depression-related behavior in RTG. Immunohistochemical analyses identified specific alterations in the expression of neurotransmitter receptors within brain regions implicated in tinnitus. Specifically, we observed a decrease in γ-aminobutyric acid A receptor α1 expression and an increase in glutamate receptor (N-methyl-D-aspartate receptor subunit 1 and receptor subunit 2B) expression in specific brain region. These changes suggest a reorganization of neural circuits associated with the tinnitus generation and behavioral changes of the rats after chronic stress exposure. Chronic stress alone can be a causal factor for the generation of tinnitus and behavioral changes through altered neural activities in tinnitus-related brain networks. NA Laryngoscope, 2024.

The ectomycorrhizal fungus Paxillus involutus positively modulates Castanea sativa Miller (var. Marsol) responses to heat and drought co-exposure

Castanea sativa Miller, a high-valuable crop for Mediterranean countries, is facing frequent and prolonged periods of heat and drought, severely affecting chestnut production. Aiming to tackle this problem, this study unraveled the influence of mycorrhizal association with the fungi Paxillus involutus (Batsch) on young chestnut plants' responses to combined heat (42 °C; 4 h/day) and drought (no irrigation until soil moisture reached 25%) over 21 days of stress exposure. Heat stress had no harmful effects on growth, photosynthesis, nor induced oxidative stress in either mycorrhizal (MR) or non-mycorrhizal (NMR) chestnut plants. However, drought (alone or combined) reduced the growth of NMR plants, affecting water content, leaf production, and foliar area, while also hampering net CO2 assimilation and carbon relations. The mycorrhizal association, however, mitigated the detrimental effects of both stresses, resulting in less susceptibility and fewer growth limitations in MR chestnut plants, which were capable of ensuring a proper carbon flow. Evaluation of the oxidative metabolism revealed increased lipid peroxidation and hydrogen peroxide levels in NMR plants under water scarcity, supporting their higher susceptibility to stress. Conversely, MR plants activated defense mechanisms by accumulating antioxidant metabolites (ascorbate, proline and glutathione), preventing oxidative damage, especially under the combined stress. Overall, drought was the most detrimental condition for chestnut growth, with heat exacerbating stress susceptibility. Moreover, mycorrhizal association with P. involutus substantially alleviated these effects by improving growth, water relations, photosynthesis, and activating defense mechanisms. Thus, this research highlights mycorrhization's potential to enhance C. sativa resilience against climate change, especially at early developmental stages.

FEATURES OF THE METABOLISM OF SIALOGLYCOPROTEINS IN THE TISSUES OF THE LIVER, STOMACH AND SMALL INTESTINE OF RATS UNDER IMMOBILIZATION STRESS

Introduction. Immobilization stress leads to the intensification of free-radical reactions leading to the destruction of sialoglycoproteins of the gastroduodenal zone. The aim of the study. To evaluate the features of the metabolism of sialoglycoproteins in the tissues of the liver, stomach and small intestine of rats under immobilization stress. Methods. Total sialic acids (TSA) and levels of sialidase activity (SA) were determined in the serum, liver, stomach, and small intestine tissues of rats by standard testing systems in dynamics on the 21st, 35th, 60th and 90th days of observation. Results. The blood serum of laboratory rats showed a maximum increase in total sialic acids and sialidases by 35 days of stress exposure, while in the liver, on the contrary, a decrease in the above-mentioned indicators. In the mucous overlays of the stomach and small intestine, the number of TSA increased throughout the dynamics of observation, and the activity of sialidase decreased by day 21 and increased in the following days of the experiment. In the wall of the stomach and small intestine of experimental rodents, the level of TSA increased by the 35th day of observation. Conclusion. During immobilization stress in the exchange of sialoglycoproteins, a compensatory predominance of anabolic processes in liver tissues was noted against the background of the prevalence of catabolism in the mucosal layer of the stomach and small intestine on days 21, 35 of observation, changes in the walls of the above organs are less pronounced and manifest themselves at a later date.

Unpredictable chronic mild stress shows neuronal remodeling in multipolar projection neurons of hippocampal complex in postnatal chicks.

The hippocampal complex of birds is a narrow-curved strip of tissue that plays a crucial role in learning, memory, spatial navigation, and emotional and sexual behavior. This study was conducted to evaluate the effect of unpredictable chronic mild stress in multipolar neurons of 3-, 5-, 7-, and 9-week-old chick's hippocampal complex. This study revealed that chronic stress results in neuronal remodeling by causing alterations in dendritic field, axonal length, secondary branching, corrected spine number, and dendritic branching at 25, 50, 75, and 100µm. Due to stress, the overall dendritic length was significantly retracted in 3-week-old chick, whereas no significant difference was observed in 5- and 7-week-old chick, but again it was significantly retracted in 9-week-old chick along with the axonal length. So, this study indicates that during initial days of stress exposure, the dendritic field shows retraction, but when the stress continues up to a certain level, the neurons undergo structural modifications so that chicks adapt and survive in stressful conditions. The repeated exposure to chronic stress for longer duration leads to the neuronal structural disruption by retraction in the dendritic length as well as axonal length. Another characteristic which leads to structural alterations is the dendritic spines which significantly decreased in all age groups of stressed chicks and eventually leads to less synaptic connections, disturbance in physiology, and neurology, which affects the learning, memory, and coping ability of an individual.

Sub-chronic stress induces similar behavioral effects in male and female mice despite sex-specific molecular adaptations in the nucleus accumbens

Women are more likely than men to suffer from major depression and anxiety disorders, a fact that is thought to depend in part on sex differences in stress susceptibility. Consistent with this, several preclinical stress paradigms have been reported to exert differential effects in males vs. females. For example, several studies have reported that female rodents are susceptible to a subset of depression- and anxiety-like behaviors induced by six days of stress exposure while males remain largely resilient. The current study sought to evaluate the generalizability of this increased vulnerability of female mice to sub-chronic stressors by examining potential sex differences in response to a new five-day stress paradigm. In addition to measuring behavior, the current work also evaluated the effects of stress on the expression of several genes in the nucleus accumbens that have been suggested to underlie sex differences in behavioral responses to sub-chronic stress. The current results indicate that males and females exhibit mostly similar behavioral alterations after exposure to this new stress model, but several sex-specific molecular alterations were observed in the nucleus accumbens following stress. Overall, our data indicate that females do not exhibit a general increase in susceptibility to ‘depression-’ and ‘anxiety-like’ behaviors induced by sub-chronic stressors, and they could reflect an example of sexual convergence in which similar behavioral alterations occur in males and females despite sex-specific molecular changes.

Chronic Social Defeat Stress Shifts Peripheral Circadian Clocks in Male Mice in a Tissue-Specific and Time-of-Day Dependent Fashion.

Uncontrollable stress is linked to the development of many diseases, some of which are associated with disrupted daily rhythms in physiology and behavior. While available data indicate that the master circadian pacemaker in the suprachiasmatic nucleus (SCN) is unaffected by stress, accumulating evidence suggest that circadian oscillators in peripheral tissues and organs can be shifted by a variety of stressors and stress hormones. In the present study, we examined effects of acute and chronic social defeat stress in mice and addressed the question of whether effects of uncontrollable stress on peripheral clocks are tissue specific and depend on time of day of stress exposure. We used mice that carry a luciferase reporter gene fused to the circadian clock gene Period2 (PER2::LUC) to examine daily rhythms of PER2 expression in various peripheral tissues. Mice were exposed to social defeat stress in the early (ZT13-14) or late (ZT21-22) dark phase, either once (acute stress) or repeatedly on 10 consecutive days (chronic stress). One hour after the last stressor, tissue samples from liver, lung, kidney, and white adipose tissue (WAT) were collected. Social defeat stress caused a phase delay of several hours in the rhythm of PER2 expression in lung and kidney, but this delay was stronger after chronic than after acute stress. Moreover, shifts only occurred after stress in the late dark phase, not in the early dark phase. PER2 rhythms in liver and WAT were not significantly shifted by social defeat, suggesting a different response of various peripheral clocks to stress. This study indicates that uncontrollable social defeat stress is capable of shifting peripheral clocks in a time of day dependent and tissue specific manner. These shifts in peripheral clocks were smaller or absent after a single stress exposure and may therefore be the consequence of a cumulative chronic stress effect.

BDNF-ОПОСРЕДОВАННЫЙ МЕХАНИЗМ АНТИСТРЕССОРНОГО ДЕЙСТВИЯ МЕЛАНОКОРТИНОВ

In recent years studies devoted to the study of the mechanisms of regulation of physiological and pathophysiological processes are of particular interest in connection with the active development of molecular medicine. Stress caused by various biological, social and technogenic factors is an integral part of modern human life and is a non-specific reaction of the body to various extreme influences. Despite the formation of adaptive mechanisms under stress in the form of generalized activation of the body, focusing of attention and memory, stress-induced analgesia, under conditions of intense and prolonged influence of a negative factor, the central nervous system loses its ability to adapt and the processes of neurogenesis are often disturbed as a result of distress. This fact explains the development of stress-induced pathological processes in the central nervous system, which emphasizes the relevance of the search and study of the mechanisms of action of pharmacological agents exhibiting stress-protective and neurotropic properties. Melanocortins (N-terminal fragments of adrenocorticotropic hormone, fragments of proopiomelanocortin and their synthetic analogs) are characterized by pronounced neurometabolic, neuroregenerative and antistress activity. One of the possible mechanisms of action of melanocortins is the influence on the levels of expression in the central nervous system of neurotrophic factors that provide the main processes of regulation of homeostasis of the body. Brain Derived Neurotrophic Factor (BDNF) which is able to reduce the negative effects of hypoxic, toxic and stressful damage to brain cells, which is due to binding to tyrosine kinase B receptor and activation of the main metabolic cascades, is one of the effective regulatory proteins. Taking into account the fact that the question of the mechanisms of the stress-protective action of substances capable of protecting brain cells from the damaging effect of stress factors is relevant, the study of the effect of melanocortins on the level of neurotrophic factors is of scientific interest. The study was carried out on 70 male white rats of 6 months of age. Sensory contact in the absence of physical contact with the subsequent formation of aggressive and submissive types of behavior was used as an experimental model of «social» stress. Laboratory animals, taking into account the gradation by types of behavior, were divided into groups: a group of control / intact animals; a group of rats exposed to «social» stress for 20 days; a group of individuals who received Semax (ACTH(4-7)-Pro-Gly-Pro) at a dose of 100 μg / kg / day intraperitoneally from the 1st day of stress exposure for a course of 20 days; a group of animals that received ACTH(6-9)-Pro-Gly-Pro at a dose of 100 μg/kg/day intraperitoneally from day 1 of stress exposure for a course of 20 days. The BDNF level in the blood serum of white rats was assessed by the enzyme-linked immunosorbent assay using ELISA Kit for Brain Derived Neurotrophic Factor (BDNF) (USA). It was found that under conditions of «social» stress, a decrease in the level of BDNF was observed. The introduction of the studied melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro) under conditions of induced «social» stress increases the concentration of BDNF in the blood serum of experimental animals. The study of the mechanisms of disturbances induced by experimental stress in various models showed that stress provokes the development of a depression-like state in rodents, which is accompanied by neuroplastic changes, including inhibition of neurogenesis in the hippocampus. Currently a large amount of experimental data has been accumulated, indicating that a pathological stress response contributes to a decrease in the level of BDNF. Deficiency of BDNF plays an important role in the pathophysiology of stress, inducing impairments of neurogenesis associated with impaired neuroplasticity, as well as dysfunction of the hypothalamic-pituitary-adrenal and neurotransmitter serotonergic systems. The effectiveness of therapy with stress protectors and antidepressants is due to their effect on neurogenesis and neuronal plasticity. Thus the fact of a decrease of BDNF under conditions of «social» stress established in the work and the positive effect of melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro), contributing to the restoration of these parameters, indicates the effect of neuropeptides on the expression of BDNF and allows us to suggest a possible mechanism of the antistress effect. It should be noted that the serum level of brain neurotrophic factor can be considered as a biomarker of stress-induced disorders and affective disorders, as well as an indicator of the effectiveness of therapy with stress protectors. In addition, the level of BDNF in the blood serum can be considered as indicators of prognosis and evaluation of the effectiveness of therapy.

Trichostatin A, a histone deacetylase inhibitor, alleviates the emotional abnormality induced by maladaptation to stress in mice

Recent reports have implied that aberrant biochemical processes in the brain are frequently accompanied by subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. The aim of the present study was to examine the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. We applied dosing schedules. In one schedule, from the 3rd day of stress exposure, mice were treated with TSA (1650 μM/4 μL, i.c.v.) immediately after the daily exposure to restraint stress. In the other schedule, from the 1st day of stress exposure, mice were treated with TSA 2 h before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using the hole-board test. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. On the other hand, no such stress adaptation was observed under chronic treatment with TSA immediately after daily stress exposure. A biochemical study showed that tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-HT) synthesis, was increased in midbrain containing raphe nuclei obtained from stress-adapted mice that were chronically treated with TSA 2 h before daily stress exposure. These findings suggest that an HDAC inhibitor may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress.

Влияние глипролинов на уровень сывороточных каспаз в условиях «социального» стресса

Objective. To investigate the effect of glyprolines on the levels of initiating and effector caspases in the serum of white rats under "social" stress. Materials and methods. The study was conducted on 90 white male rats of 6 months of age. All manipulations with animals were carried out in accordance with international and domestic requirements for working with laboratory animals. When modeling "social" stress, groups of animals with aggressive and submissive behavior were formed. Laboratory animals, taking into account the types of behavior, were divided into groups (n=10): a group of intact males (control); a group of animals exposed to" social " stress for 20 days (stress); groups of individuals who received intraperitoneal Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), Pro-Gly-Pro, Pro-Gly-Pro-Leu at doses of 100 mcg/kg / day from the 1st day of stress exposure within a 20- day course. The effect of neuropeptides on the activity of apoptosis processes was evaluated by determining the level of initiating and effector caspases (caspase-8 and caspase-3) (ELISA Kit for Caspase-8 and ELISA Kit for Caspase-3; USA) in the blood serum of white rats by enzyme immunoassay. Results. According to the results of the study, it was found that under conditions of "social" stress, an increase in apoptotic processes was observed, accompanied by an increase in the level of caspase-3 and caspase-8 in the blood serum of white rats. The introduction of the studied compounds against the background of stress contributed to a decrease in the level of the studied indicators, which is most likely due to the presence of antiapoptotic action in glyprolins due to inhibition of the caspase-dependent cascade of apoptosis reactions, as a result of which the destruction of cellular structures occurs by hydrolysis of nuclear lamina, cleavage of adhesive proteins, destruction of the cytoskeleton. Conclusion. Thus, the conducted study established the presence of Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selank), Pro-Gly-Pro and Pro-Gly-Pro-Leu under conditions of stress-induced antiapoptotic activity due to inhibition of the caspase-dependent cascade of apoptosis reactions.

Lifelong enhancement of body mass from adolescent stress in male hamsters

In hamsters, exposure to stress in adulthood causes increased body weight. We addressed how social stress during puberty would impact food intake and body weight. Stressed hamsters started gaining significantly more weight than controls after only two days of stress exposure. Over a two-week period, stressed subjects gained 10% more weight and consumed more food than controls. At the end of the stress period, stressed hamsters collected nearly twice as many palatable sugar pellets from an arena than controls. Stressed subjects presented 15–20% more body fat in mesenteric, inguinal, and retroperitoneal fat pads. In order to assess the duration of these effects, we analyzed data from previous studies keeping hamsters for over two months past the stress period in puberty. Our analysis shows that stressed hamsters stopped gaining more weight after the stress period, but their body weights remained elevated for over two months, consistently weighing 10% more than their non-stressed counterparts. We also analyzed conditioning training data collected after the period of stress in late puberty and early adulthood (P56 to P70) that was part of the original studies. Training consisted of lever pressing for palatable food rewards. At these times, previously stressed hamsters retrieved similar numbers of food pellets from the conditioning chambers, suggesting no difference in appetite after the stress period. These data showing a long-lasting effect of stress on body weight may be relevant to studies on the ontogeny of lifelong obesity.

EFFECT OF GLYPROLINES ON THE LEVEL OF NERVE GROWTH FACTOR UNDER CONDITIONS OF "SOCIAL" STRESS

Today a study aimed at the role of various neurotrophic factors in the implementation of a stress response and their influence on the functioning of the central and peripheral nervous system is of particular interest. Nerve growth factor (NGF) which belongs to a special group of polypeptide regulators has the most expressed neurospecificity. It has been established that this factor has a neuroprotective effect which is realized due to its ability to induce the induction of antiapoptotic proteins and inhibition of proapoptotic ones, thereby affecting the survival rate, as well as the differentiation of individual populations of peripheral neurons. Currently neuropeptide drugs with a wide spectrum of biological activity are considered as the leading stress protectors. Glyproline neuropeptides with proven versatile pharmacological activity, namely neuroprotective, anti-inflammatory, regenerative, immunotropic, etc., attract particular attention. Objective: to study the effect of glyprolines on the level of nerve growth (NGF) in the blood serum of white rats under conditions of "social" stress. Materials and methods. The study was carried out on 90 white non-linear male rats for 6 months. The experimental model of "social" stress was formed as a result of sensory contact for 20 days, followed by the formation of aggressive and submissive types of behavior. Glyproline compounds Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selank), Pro-Gly-Pro and Pro-Gly-Pro-Leu were injected intraperitoneally at a dose of 100 pg/kg/day from the 1st day of stress exposure by the course 20 days. The level of NGF in the blood serum of white rats was assessed by the enzyme-linked immunosorbent assay using an ELISA Kit for NGF (USA). Results. Exposure to "social stress" led to a decrease in the level of nerve growth factor which probably has a cause-and-effect relationship with a decrease in neurogenetic processes. The observed restoration of the NGF level under the influence of glyprolines Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selank), Pro-Gly-Pro and Pro-Gly-Pro-Leu indicates their stress and neuroprotective activity.

Sex differences in stress-induced sleep deficits

Sleep disruptions are hallmarks in the pathophysiology of several stress-related disorders, including Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD), both known to disproportionately affect female populations. Although previous studies have attempted to investigate disordered sleep in women, few studies have explored and compared how repeated stress affects sleep in both sexes in either human or animal models. We have previously shown that male rats exhibit behavioral and neuroendocrine habituation to 5 days of repeated restraint, whereas females do not; additional days of stress exposure are required to observe habituation in females. This study examined sex differences in sleep measures prior to, during, and after repeated restraint stress in adult male and female rats. Our data reveal that repeated stress increased time spent awake and decreased slow-wave sleep (SWS) and REM sleep (REMS) in females, and these effects persisted over 2 days of recovery. In contrast, the effects of stress on males were transient. These insomnia-like symptoms were accompanied by a greater number of exaggerated motor responses to waking from REMS in females, a phenotype similar to trauma-related nightmares. In sum, these data demonstrate that repeated stress produces disruptions in sleep that persist days after the stress is terminated in female rats. These disruptions in sleep produced by 5 days of repeated restraint may be due to their lack of habituation.

EFFECTS OF MELANOCORTINSON THE BEHAVIOR OF RATSIN THETEST OFELEVATED CRUCIFORM MAZE AND EXPERIMENTALLY INDUCED OFSOCIALS

— In this study we have investigated the effects of melanocortins (group analogs of neuropeptides) on the psychoemotional state of rats under conditions of experimental social stress. The study was carried out on male rats which were injected intraperitoneally for 20 days with the neuropeptide drugs Semax and ACTH(6-9)-ProGly-Pro at a dose of 100 μg/kg/day starting from the 1st day of stress exposure. The psychoemotional state of the animals was evaluated by means of the behavioral test of elevated cruciform maze. It was found that intraperitoneal administration of neuropeptides (Semax, ACTH(6-9)- Pro-Gly-Pro) helps to reduce high anxiety levels in animals both with aggressive and submissive types of behavior under conditions of experimental social stress via their psychomodulatory effects.

Moderate Adolescent Ethanol Vapor Exposure and Acute Stress in Adulthood: Sex-Dependent Effects on Social Behavior and Ethanol Intake in Sprague-Dawley Rats.

Adolescent alcohol use can lead to numerous consequences, including altered stress reactivity and higher risk for later anxiety and alcohol use disorders. Many studies have examined the consequences of heavy ethanol exposure in adolescence, but far less is understood about lower levels of intoxication. The present study examined moderate adolescent ethanol exposure as a possible factor in increasing stress reactivity in adulthood, measured through general and social anxiety-like behaviors, as well voluntary ethanol intake. Male and female Sprague–Dawley rats underwent an adolescent chronic intermittent ethanol (aCIE) vapor exposure during early adolescence, reaching moderate blood ethanol concentrations. Animals then underwent two days of forced swim stress in adulthood. We found that ethanol-exposed males consumed more ethanol than their air counterparts and an interesting stress and ethanol exposure interaction in males. There were no significant effects on voluntary drinking in females. However, the social interaction test revealed increased play-fighting behavior in ethanol-exposed females and reduced social preference in females after two days of stress exposure. Overall, this work provides evidence for sex-specific, long-term effects of moderate aCIE and susceptibility to acute stress in adulthood.

Reduced positive affect on days with stress exposure predicts depression, anxiety disorders, and low trait positive affect 7 years later.

Positive emotions serve important functions for mental health. Susceptibility to reduced positive emotions in the context of stress may increase risk for poor mental health outcomes, including anxiety and depressive disorders and low overall levels of positive emotion. In an 8-day daily diary study within a larger panel study (N = 1,517), we tested whether degree of reduction in time spent experiencing positive affect on days of stress exposure predicted lower levels of positive affect and elevated risk for major depressive and anxiety disorders (generalized anxiety disorder or panic disorder) 7 years later. Bayesian multilevel structural equation modeling controlling for overall levels of affect, stress exposure, leisure time, sex, age, and past year diagnoses of depression and anxiety disorders was conducted. Participants, on average, reported less time experiencing positive affect on days with stressors compared to days without stressors. In addition, participants varied in the extent to which their time spent experiencing positive affect differed across days with and without stressors. Those who reported an especially reduced proportion of the day experiencing positive affect on days with stressors also experienced lower positive affect and greater risk for major depressive disorder and anxiety disorders 7 years later. These prospective associations suggest that between-person differences in the within-person association between stress and positive emotions have implications for mental health years later. The efficacy of preventive interventions could be improved by fostering resilience of positive emotions during common stressful events. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Sex differences in the regulation of brain IL-1β in response to chronic stress

Elevations in brain interleukin-1 beta (IL-1β) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1β production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: β-AR) IL-1β production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the “yin-yang” balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1β. To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (β-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1β mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1β expression in non-stressed controls but significantly reduced IL-1β in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1β in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1β mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1β in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1β indicating the increase in brain IL-1β following metyrapone treatment was due to increase β-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL-1β. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1β by the norepinephrine-β-AR pathway, while stress had no effect in the regulation of brain IL-1β in female rats.

Intermittent hypoxia improves behavioral and adrenal gland dysfunction induced by posttraumatic stress disorder in rats.

Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.

Hippocampal CA1 Neuronal and Sympathetic Nerve Activities in Response to Restraint Water‐Immersion Stress in Conscious Rats

The hippocampus has been suggested to play a significant role in adaptation to chronic stress. However, there has been lack of direct evidence for responses of hippocampal neuronal activity to chronic stress. The present study was aimed to record hippocampal CA1 neuronal and sympathetic nerve activities during chronic stress. Wistar rats were instrumented chronically with a combined probe made with multiple electrodes (100 micrometer stainless steel wires) for measurement of hippocampal CA1 neuronal activity and glass fiber for measurement of hippocampal cerebral blood flow (CBF), electrodes for measurements of renal (RSNA) and lumbar (LSNA) sympathetic nerve activity, and electroencephalogram, electromyogram, and electrocardiogram and with catheter for measurement of systemic arterial pressure (AP). Rats were exposed repeatedly to restraint water‐immersion stress (RWIS) for 90 min/day over 5 days. Hippocampal CA1 neuronal activity, RSNA, and LSNA were measured continuously and simultaneously before, during, and after RWIS. Hippocampal CA1 neuronal activity decreased immediately after onset of RWIS and the decreased level was maintained throughout the 90 min of RWIS on the first day of stress exposure. On day 5 of RWIS, hippocampal CA1 neuronal activity decreased immediately after onset of RWIS, however it gradually recovered to the control level during the RWIS period. Thus, hippocampal CA1 neurons gradually adapted to the repeated RWIS exposure while RSNA and LSNA increased immediately after the onset of RWIS and showed no adaptive response during repeated exposure to RWIS.Support or Funding InformationJSPS GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Homoeolog-specific activation of genes for heat acclimation in the allopolyploid grass Brachypodium hybridum.

BackgroundAllopolyploid plants often show wider environmental tolerances than their ancestors; this is expected to be due to the merger of multiple distinct genomes with a fixed heterozygosity. The complex homoeologous gene expression could have been evolutionarily advantageous for the adaptation of allopolyploid plants. Despite multiple previous studies reporting homoeolog-specific gene expression in allopolyploid species, there are no clear examples of homoeolog-specific function in acclimation to a long-term stress condition.ResultsWe found that the allopolyploid grass Brachypodium hybridum and its ancestor Brachypodium stacei show long-term heat stress tolerance, unlike its other ancestor, Brachypodium distachyon. To understand the physiological traits of B. hybridum, we compared the transcriptome of the 3 Brachypodium species grown under normal and heat stress conditions. We found that the expression patterns of approximately 26% and approximately 38% of the homoeolog groups in B. hybridum changed toward nonadditive expression and nonancestral expression, respectively, under normal condition. Moreover, we found that B. distachyon showed similar expression patterns between normal and heat stress conditions, whereas B. hybridum and B. stacei significantly altered their transcriptome in response to heat after 3 days of stress exposure, and homoeologs that were inherited from B. stacei may have contributed to the transcriptional stress response to heat in B. hybridum. After 15 days of heat exposure, B. hybridum and B. stacei maintained transcriptional states similar to those under normal conditions. These results suggest that an earlier response to heat that was specific to homoeologs originating from B. stacei contributed to cellular homeostasis under long-term heat stress in B. hybridum.ConclusionsOur results provide insights into different regulatory events of the homoeo-transcriptome that are associated with stress acclimation in allopolyploid plants.

Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway Is Associated with Hypothalamic Neuronal Injury in Different Durations of Stress in Rats.

The hypothalamus, which is the initial part of the hypothalamic-pituitary-adrenal (HPA) axis, plays a critical role in regulating stress in the central nervous system. The present study aimed to determine whether endoplasmic reticulum stress in hypothalamic neurons is differentially stimulated by varying durations of stress exposure, which ultimately leads to pathological changes in neurons by affecting HPA axis function. There is a need for better morphological evidence of the mechanisms involved in stress-induced neuron injury. A stress model was established in rats by restraining for 8 h and forced ice-water swimming for 5 min each day. The stress-inducing process lasted for 1, 3, 7, 14, and 21 days. Enzyme-linked immunosorbent assay (ELISA) was used to assay serum glucocorticoid levels. Thionine staining was used to observe morphological changes in hypothalamic neurons. Immunohistochemistry and microscopy-based multicolor tissue cytometry (MMTC) was used to detect changes in expression of endoplasmic reticulum stress protein GRP78, ATF4, and CHOP. Serum glucocorticoid levels significantly increased after 3 days of stress exposure and the levels peaked by 7 days. By 21 days, however, the levels were significantly decreased. Thionine staining revealed that prolonged stress exposure resulted in hypothalamic neurons with edema, a lack of Nissl bodies, and pyknotic neurons. Immunohistochemistry and MMTC showed that increasing stress periods significantly decreased GRP78 expression, although ATF4 and CHOP protein expression significantly increased. Stress resulted in pathological changes and significant dynamic changes because of endoplasmic reticulum stress in rat hypothalamic neurons. These results suggested that the endoplasmic reticulum stress PERK-ATF4-CHOP pathway may be associated with hypothalamic neuronal injury.