Chronic Variable Stress Exposure Research Articles

Intermittent sucrose solution intake and its schedule of access modulate energy intake and weight gain in response to chronic variable stress in mice

There is a strong relationship between stress and the intake of calorically-dense palatable food. Additionally, intake of sodas is an important contributory factor to obesity, and is often associated with palatable food consumption. We studied the effects of 2-h intermittent access to sucrose-sweetened water (SSW, 12.3%, soda-like) and its schedule of administration on the response to chronic variable stress in mice fed a high-fat, high-sugar diet. C57BL/6 mice (n = 64) had access to water or to both water and 2-h SSW during 5 weeks, in addition to their diet. After the first two weeks, half of the animals from each group were stressed daily using a chronic variable stress (CVS) paradigm, while the other half were kept undisturbed. During the CVS exposure period, 2-h SSW access was either scheduled randomly, right before the stressors or right after the stressors. The effects of SSW and its schedule of administration on dietary intake, stress hormones and adiposity were analyzed. Results showed a larger consumption of SSW and higher bodyweight gain in mice receiving SSW after the stressor. In addition, SSW consumption was shown to affect appetite regulation by reducing CCK sensitivity. The present study suggests that SSW leads to overconsumption and weight gain only if provided after exposure to stress. These findings may implicate a relation between exposure to stress, binge-drinking behaviors of sugar sweetened beverages that ensues, and weight gain in humans consuming a western diet.

Dietary phytochemicals modulate experience-dependent changes in Neurexin gene expression and alternative splicing in mice after chronic variable stress exposure

Neurexins (NRXNs) are cell-adhesion molecules important in the formation and remodeling of neural circuits. It has been shown that aversive environmental stimuli can affect the expression pattern of Neurexin genes (Nrxns) impacting the regulation of synaptic strength. Accumulated evidence suggests that, after chronic exposure to psychological stress, the triggered changes in gene expression and splicing patterns of Nrxns may be involved in aversive conditioning. Previously, we have demonstrated that a novel treatment using dietary phytochemicals can modulate the response to chronic variable stress (CVS) in mice. Here, we aimed to further investigate the long-term plasticity changes after CVS by focusing on the regulation of NRXNs at synapses. We found that CVS differentially triggers the region-specific gene expression of Nrxns in mice Nucleus Accumbens (NAc) and Hippocampus (HIPP). The prophylactic treatment with the combination of two phytochemicals dihydrocaffeic acid (DHCA) and Malvidin-3-O-glucoside (Mal-gluc) differentially modulated the stress-induced effects on Nrxn1 and 3 mRNA expression in these brain areas and promoted the alternative splicing of Nrxn3 in HIPP.Overall, our data supports the prophylactic effect of dietary phytochemicals in the restoration of stress-induced plasticity changes in mouse brain. By intervening in activity-dependent plasticity at synapses, these compounds may attenuate the effects of chronic aversive conditioning. We propose that an early therapeutic intervention may help with disorders of negative affect, such as depression or post-traumatic stress disorder. Our future studies will address how DHCA/Mal-gluc might serve as a potential complement for current therapies in depression and other mood disorders.

Vitamin C supplementation during chronic variable stress exposure modulates contractile functions of testicular artery and sperm parameters in male Wistar rats

BackgroundHumans are exposed to identifiable multiple environmental stressors. However, there is paucity of studies assessing chronic variable stress (CVS) exposure together with antioxidant supplementation on reproductive function. This study investigates impact of vitamin C supplementation, during CVS exposure on contractile functions of testicular artery and sperm parameters. Twenty pubertal male Wistar rats (150–200 g) were grouped into four of five rats each consisting of control (normal saline), vitamin C treated (7 mg/kg bwt), chronic variable stress (CVS) + vitamin C, and CVS only. Animals were treated respectively for 8 weeks. Serum superoxide dismutase (SOD), catalase, malondialdehyde (MDA) activity, testosterone, and cortisol were assayed. Contractile responses of excised testicular artery to phenylephrine, potassium chloride, acetylcholine, and sodium nitroprusside were determined using Ugo Basile data acquisition system. Sperm parameters and histopathology of the testis were also determined. Statistical significance was taken at p < 0.05ResultMDA activity was significantly increased in group exposed to chronic variable stress. However, groups supplemented with vitamin C during CVS exposure showed no significant increase. Serum SOD and catalase were enhanced in group exposed to CVS with vitamin C supplementation when compared to group exposed to chronic variable stress only. Chronic variable stress exposure increased serum cortisol level and this was attenuated with vitamin C supplementation. Vitamin C supplementation significantly increased serum testosterone level when compared to CVS only exposed group. Contraction responses of testicular arterial strips to phenylephrine and potassium chloride were attenuated in vitamin C supplemented groups when compared to CVS only exposed group. Vitamin C supplementation during CVS exposure also enhanced relaxation of testicular artery strip to sodium nitroprusside and acetylcholine. Sperm count and percentage motility were significantly reduced in CVS only exposed group when compared vitamin C supplemented group. Sperms cells with abnormal morphology were also significantly increased in chronic variable stress only exposed group when compared to control and vitamin C supplemented groups.ConclusionChronic variable stress adversely impacts contractility of testicular artery, sperm parameters, cortisol, and testosterone level. Vitamin C supplementation modulated these by suppressing MDA and enhancing antioxidant enzyme activity.

Chronic stress leads to long-lasting deficits in olfactory-guided behaviors, and to neuroplastic changes in the nucleus of the lateral olfactory tract

A recent study reported that the integrity of the nucleus of the lateral olfactory tract (nLOT) is required for normal olfaction and for the display of odor-driven behaviors that are critical for species survival and reproduction. In addition to being bi-directionally connected with a key element of the neural circuitry that mediates stress response, the basolateral nucleus of the amygdala, the nLOT is a potential target for glucocorticoids as its cells express glucocorticoid receptors. Herein, we have addressed this hypothesis by exploring, first, if chronic variable stress (CVS) disrupts odor detection and discrimination, and innate olfactory-driven behaviors, namely predator avoidance, sexual behavior and aggression in male rats. Next, we examined if CVS alters the nLOT structure and if such changes can be ascribed to stress-induced effects on the activity of the main output neurons, which are glutamatergic, and/or of local GABAergic interneurons. Finally, we analyzed if the stress-induced changes are transient or, conversely, persist after cessation of CVS exposure. Our data demonstrate that CVS leads to severe olfactory deficits with inability to detect and discriminate between odors and to innately avoid predator odors. No effects of CVS on sexual and aggressive behaviors were observed. Results also showed that CVS leads to somatic hypertrophy of pyramidal glutamatergic neurons, which likely results from neuronal disinhibition consequent to the loss of inhibitory inputs mediated by GABAergic interneurons. Most of the CVS-induced effects persist beyond a 4-week stress-free period, suggesting long-lasting effects of chronic stress on the structure and function of the olfactory system.

Chronic variable stress and intravenous methamphetamine self-administration – Role of individual differences in behavioral and physiological reactivity to novelty

Stress is a contributing factor to the development and maintenance of addiction in humans. However, few studies have shown that stress potentiates the rewarding and/or reinforcing effects of methamphetamine in rodent models of addiction. The present study assessed the effects of exposure to 14 days of chronic variable stress (CVS), or no stress as a control (CON), on the rewarding and reinforcing effects of methamphetamine in adult rats using the conditioned place preference (Experiment 1) and intravenous self-administration (Experiment 2) paradigms. In Experiment 2, we also assessed individual differences in open field locomotor activity, anxiety-like behavior in the elevated plus maze (EPM), and physiological responses to a novel environment as possible predictors of methamphetamine intake patterns. Exposure to CVS for 14 days did not affect overall measures of methamphetamine conditioned reward or reinforcement. However, analyses of individual differences and direct vs. indirect effects revealed that rats exhibiting high physiological reactivity and locomotor activity in the EPM and open field tests self-administered more methamphetamine and reached higher breakpoints for drug reinforcement than rats exhibiting low reactivity. In addition, CVS exposure significantly increased the proportion of rats that exhibited high reactivity, and high reactivity was significantly correlated with increased levels of methamphetamine intake. These findings suggest that individual differences in physiological and locomotor reactivity to novel environments, as well as their interactions with stress history, predict patterns of drug intake in rodent models of methamphetamine addiction. Such predictors may eventually inform future strategies for implementing individualized treatment strategies for amphetamine use disorders.

Chronic variable stress exposure in male Wistar rats affects the first step of olfactory detection

For most animal species, olfaction plays a paramount role in their perception of the environment. Odours are initially detected in neurons located in the olfactory mucosa. This tissue is regulated by several physiological signals and can be altered in pathology. A number of clinical studies suggest an association between depressive disorders and olfactory sensory loss. In rodents, depressive-like states can be observed in models of chronic stress. We tested the hypothesis that olfactory function might be altered in a rat model of depression, induced by chronic variable stress (CVS). While CVS rats exhibited several symptoms consistent with chronic stress exposure and depressive-like states (increased sucrose intake in sucrose preference test, increased immobility in forced swim test, hyperlocomotion), their odorant responses recorded at the olfactory mucosa level by electro-olfactogram were decreased. In addition we observed increased apoptosis markers in the olfactory mucosa using Western Blot. Our data are consistent with reduced olfactory capacities in a laboratory rat model of chronic stress and depression, in agreement with human clinical data; this warrants further mechanistic studies. Furthermore, this works raises the possibility that altered olfactory function might be a confounding factor in the behavioural testing of chronically stressed or depressed rats.

Sucrose Solution Intake and its Schedule of Access Affect the Response to Chronic Variable Stress in Mice

There is a strong relationship between the intake of calorically-dense palatable food and stress. Moreover, intake of sodas is an important contributory factor to obesity, and is often associated with palatable food consumption. We studied the effects of 2-hour intermittent access to sucrose-sweetened water (SSW, 12.3%, soda-like) and its schedule of administration on the response to chronic variable stress in mice fed a high-fat, high-sugar diet. C57BL/6 mice received access to water or to both water and 2-hour SSW access during 5 weeks, in addition to their diet. After the first two weeks, half of the animals from each group were stressed daily using a chronic variable stress (CVS) paradigm, while the other half were kept undisturbed. During the CVS exposure period, SSW access was either scheduled randomly, right before the stressors or right after the stressor The effects of SSW and its schedule of administration on stress hormones, adiposity and serum lipids were analyzed. Results showed that SSW access induced an increase in energy intake, body weight gain and abdominal fat as well as attenuation in the response to CVS compared to water access alone. Moreover, there was a greater stress-relieving effect when SSW was administered after exposure to the stressors, compared to random exposure and exposure before the stressors. The present study provides arguments that the availability of intermittent SSW access renders mice more resilient to the effects of CVS, particularly when SSW is provided after exposure to stress.

Stress Vulnerability during Adolescent Development in Rats

Adolescent development is proposed to represent a time of increased susceptibility to stress. During adolescence, the brain demonstrates a high level of plasticity and can be positively or negatively affected by the environment. This study tests the hypothesis that adolescent development is a stage of enhanced vulnerability to chronic stress. Male Sprague-Dawley rats were exposed to our 14-d chronic variable stress (CVS) paradigm at three developmental stages: 1) early adolescence (35 d; age at initiation of CVS); 2) late adolescence (50 d); or 3) adulthood (80 d). We examined the effects of CVS on the following: 1) depression-like behavior; 2) somatic indices; 3) hypothalamic-pituitary-adrenal (HPA) axis activity; and 4) neuropeptide expression in the hypothalamus. Results show, regardless of age, CVS exposure: 1) decreased body weight; 2) increased adrenal size; 3) decreased fat weight; and 4) increased HPA response to stress. The somatic effects of CVS were exaggerated in late adolescent animals, and late adolescent animals were the only group where CVS decreased oxytocin expression and increased basal corticosterone. In response to CVS, adult animals increased immobility during the forced-swim test while early and late adolescent animals were resistant to the effects of chronic stress on depression-like behavior. Results show that adolescent animals were protected from the effect of chronic stress on depression-like behavior while late adolescent animals were more susceptible to the somatic, HPA axis, and neuropeptide effects of chronic stress. Thus, adolescent development is a unique window of vulnerabilities and protections to the effects of chronic stress.

The medial amygdala modulates body weight but not neuroendocrine responses to chronic stress.

Stress pathologies such as depression and eating disorders (i.e. anorexia nervosa) are associated with amygdalar dysfunction, which are linked with hypothalamic-pituitary-adrenal axis (HPA) axis hyperactivity. The medial amygdaloid nucleus (MeA), a key output nucleus of the amygdaloid complex, promotes HPA axis activation to acute psychogenic stress and is in a prime position to mediate the deleterious effects of chronic stress on physiology and behaviour. The present study tests the hypothesis that the MeA is necessary for the development of maladaptive physiological changes caused by prolonged stress exposure. Male rats received bilateral ibotenate or sham lesions targeting the MeA and one half underwent 2 weeks of chronic variable stress (CVS) or served as home cage controls. Sixteen hours post CVS, all animals were exposed to an acute restraint challenge. CVS induced thymic involution, adrenal hypertrophy, and attenuated body weight gain and up-regulation of hypothalamic corticotrophin-releasing hormone mRNA expression. Consistent with previous literature, lesions of the MeA dampened stress-induced increases in corticosterone after 30 min of exposure to acute restraint stress. However, this effect was independent of CVS exposure, suggesting that the MeA may not be critical for modulating neuroendocrine responses after chronic HPA axis drive. Interestingly, lesion of the MeA modestly exaggerated the stress-induced attenuation of weight gain. Overall, the data obtained suggest that the MeA modulates the neuroendocrine responses to acute but not chronic stress. In addition, the data suggest that the MeA may be an important neural component for the control of body weight in the face of chronic stress.

Aging increases the susceptibility to develop anhedonia in male rats

The objective of this study was to establish the effect of aging on the development of anhedonia, a core feature of depression. Young and old male Wistar rats (of around 3–5 and 12–15 months, respectively) were exposed to a chronic variable stress (CVS) schedule for 3 weeks. CVS produced anhedonia, indicated by a reduction in the intake of a sucrose solution (1%), in 8 out of 23 (35%) young rats and in 19 out of 26 (73%) old rats, implying that old animals are more susceptible to stress and develop anhedonia more readily than young animals. Young and old anhedonic rats showed a similar temporal course in the reduction of sucrose consumption, reaching the anhedonic state after 2 weeks of CVS exposure. Compared with young animals, old rats had lower basal serum testosterone and estradiol levels. The systemic levels of corticosterone did not vary between both age groups. No significant pathological condition was detected in old animals. It is suggested that the higher susceptibility to develop anhedonia in male rats could be associated to neuroendocrine changes consequent to aging.

The Anteroventral Bed Nucleus of the Stria Terminalis Differentially Regulates Hypothalamic-Pituitary-Adrenocortical Axis Responses to Acute and Chronic Stress

The anteroventral region of the bed nucleus of the stria terminalis (BST) stimulates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress. However, the role of the anterior BST nuclei in chronic drive of the HPA axis has yet to be established. Therefore, this study tests the role of the anteroventral BST in physiological responses to chronic drive, using a chronic variable stress (CVS) model. Male Sprague-Dawley rats received either bilateral ibotenate lesions, targeting the anteroventral BST, or vehicle injection into the same region. Half of the lesion and control rats were exposed to a 14-d CVS paradigm consisting of twice-daily exposure to unpredictable, alternating stressors. The remaining rats were nonhandled control animals that remained in home cages. On the morning after the end of CVS exposure, all rats were exposed to a novel restraint stress challenge. CVS induced attenuated body weight gain, adrenal hypertrophy, thymic involution, and enhanced CRH mRNA in hypophysiotrophic neurons of the hypothalamic paraventricular nucleus, none of which were affected by anteroventral BST lesions. In the absence of CVS, lesions attenuated the plasma corticosterone and paraventricular nucleus c-fos mRNA responses to the acute restraint stress. In contrast, lesions of the anteroventral BST elevated plasma ACTH and corticosterone responses to novel restraint in the rats previously exposed to CVS. These data suggest that the anterior BST plays very different roles in integrating acute stimulation and chronic drive of the HPA axis, perhaps mediated by chronic stress-induced recruitment of distinct BST cell groups or functional reorganization of stress-integrative circuits.

Early exposure to chronic variable stress facilitates the occurrence of anhedonia and enhanced emotional reactions to novel stressors: reversal by naltrexone pretreatment

The present research studied the influence of an early chronic variable stress (CVS) paradigm — an animal model of depression — on behavioral responses to subsequent environmental challenges suggested to model anhedonia and emotional reactions such as anxiety and fear. In order to explore a potential involvement of an endogenous opiate mechanism — presumably activated during CVS exposure — in the development of such behavioral reactions, in all experiments rats were administered naltrexone (NAL, 2 mg/kg, i.p.) or vehicle (VH) prior to each daily stressor of the CVS procedure. Animals were exposed to CVS and 1 week later tested for sucrose preference (1%) in a free choice paradigm after the presentation or not of a 90-min restraint period. Only CVS treated animals that were later exposed to restraint showed a reduction of sucrose preference, this reduction was absent when CVS rats were pretreated previously with NAL. Moreover, CVS rats were one week later tested on the elevated plus maze (EPM) and in their conditioned and unconditioned freezing response to a single shock session. Early chronic stress resulted in an anxiogenic behavior in the EPM and in an enhanced conditioned and unconditioned freezing which were all abolished by NAL pretreatment. These behavioral findings suggest that the potential activation of an endogenous opiate mechanism during CVS participates in the development of anhedonia and exaggerated emotional reactions in response to subsequent stressful experiences.

The involvement of an opiate mechanism in the sensitized behavioral deficit induced by early chronic variable stress: Influence of desipramine

The influence of early chronic variable stress (CVS) associated with persistent desipramine (DMI) administration was examined on escape performance. Animals were exposed to CVS and 1 day later administered DMI (5 mg/kg, i.p. twice a day) or vehicle (VH) during six consecutive days. Escape performance was assessed over 24 h following inescapable shock (IS) exposure. Higher escape failures were observed in CVS shocked rats compared with unstressed shocked animals. DMI normalized escape failures in both groups. In order to investigate the role of an endogenous opiate mechanism presumably activated by CVS exposure in this behavioral deficit, rats were administered naltrexone (NAL, 2 mg/kg i.p.) or VH prior to each daily stressor of the CVS regime. NAL pretreatment blocked escape failures performed only by CVS shocked rats. In addition, animals were daily administered morphine (MOR, 10 mg/kg, i.p.) or VH during seven consecutive days and subsequently administered DMI. A significant increase in escape deficit in shocked rats was observed after chronic MOR but not following the associated treatment with MOR and DMI. These behavioral data suggest that early experience with a CVS facilitated the onset of escape deficit induced by a brief IS event, an effect that can be prevented by chronic DMI. Furthermore, this sensitized escape deficit response seems to be partially modulated by the previous activation of an opiate mechanism.