Effects Of Chronic Unpredictable Stress Research Articles

Physiological and behavioral contagion/buffering effects of chronic unpredictable stress in a socially enriched environment: A preliminary study

Rodents are sensitive to the emotional state of conspecifics. While the presence of affiliative social partners mitigates the physiological response to stressors (buffering), the partners of stressed individuals show behavioral and endocrine changes indicating that stress parameters can be transmitted across the group members (contagion). In this study, we investigated the social contagion/buffering phenomena in behavior and neuroendocrine mechanisms after exposure to chronic stress, in groups of rats living in the PhenoWorld (PhW). Three groups were tested (8 stressed rats, 8 unstressed rats, and a mixed group with 4 and 4) and these were analyzed under 4 conditions: stressed (pure stress group, n = 8), unstressed (naive control group, n = 8), stressed from mixed group (stressed companion group, n = 8), unstressed from mixed group (unstressed companion group, n = 8. While naive control animals remained undisturbed, pure stress group animals were all exposed to stress. Half of the animals under the mixed-treatment condition were exposed to stress (stressed companion group) and cohabitated with their unstressed partners (unstressed companion group). We confirmed the well-established chronic unpredictable stress (CUS) effects in physiological, behavioral, and neuroendocrine endpoints; body weight gain, open arm entries and time in EPM, and oxytocin receptor expression levels in the amygdala decreased by stress exposure, whereas adrenal weight was increased by stress. Furthermore, we found that playing, rearing and solitary resting behaviors decreased, whereas huddling behavior increased by CUS. In addition, we detected significant increases (stress-buffering) in body weight gain and huddling behaviors between pure stress and stress companion animals, and significant stress contagion effects in emotional behavior and oxytocin receptor expression levels between naive control and control companion groups. Hence, we demonstrate buffering and contagion effects were evident in physiological parameters, emotional behaviors, and social home-cage behaviors of rats and we suggest a possible mediation of these effects by oxytocin neurotransmission. In conclusion, the results herein suggest that the stress status of animals living in the same housing environment influences the behavior of the group.

NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia.

The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan, from axonal growth and guidance to spine and synaptic pruning, to organization of proteins at the nodes of Ranvier. NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia. Here we investigated the effects of chronic unpredictable stress on latent inhibition, a measure of selective attention and learning which shows alterations in schizophrenia, in NrCAM knockout (KO) mice and their wild-type littermate controls (WT). Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001). However, following chronic unpredictable stress, WT mice (p = 0.002), but not NrCAM KO mice (F < 1), expressed latent inhibition. Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001), a single hit by stress in Acb-shell (p = 0.031), a dual hit stress x genotype in mOFC (p = 0.008), vOFC (p = 0.020), and Acb-core (p = 0.032), and no effect in PrL cortex (p > 0.141). These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

Effect of chronic unpredictable stress in female Wistar-Kyoto rats subjected to progesterone withdrawal: Relevance for Premenstrual Dysphoric Disorder neurobiology

Premenstrual Dysphoric Disorder (PMDD) is related to an abrupt drop in progesterone and impairments in the HPA axis that cause anxiety. Suffering persons report higher daily-life stress and anxiety proneness that may contribute to developing PMDD, considered a chronic stress-related disorder. Here, we explored the effect of chronic unpredictable stress (CUS) in rats subjected to progesterone withdrawal (PW) and evaluated gene expression of HPA axis activation in the stress-vulnerable Wistar-Kyoto (WKY) rat strain that is prone to anxiety. Ovariectomized WKY rats were randomly assigned to CUS or Standard-housed conditions (SHC) for 30 days. To induce PW, animals received 2 mg/kg of progesterone on day 25th for 5 days; 24 h later, they were tested using the anxiety-like burying behavior test (BBT). After behavioral completion, rats were euthanized, and brains were extracted to measure Crh (PVN) and Nr3c1 (hippocampus) mRNA. Blood corticosterone and vasopressin levels were determined. Results showed that PW exacerbated anxiety-like behaviors through passive coping in CUS-WKY. PW decreased Crh-PVN mRNA and the Nr3c1-hippocampal mRNA expression in SHC. CUS decreased Crh-PVN mRNA compared to SHC, and no further changes were observed by PW or BBT exposure. CUS reduced Nr3c1-hippocampal gene expression compared to SHC animals, and lower Nr3c1 mRNA was detected due to BBT. The PW increased corticosterone in SHC and CUS rats; however, CUS blunted corticosterone when combined with PW+BBT and similarly occurred in vasopressin concentrations. Chronic stress blunts the response of components of the HPA axis regulation when PW and BBT (systemic and psychogenic stressors, respectively) are presented. This response may facilitate less adaptive behaviors through passive coping in stress-vulnerable subjects in a preclinical model of premenstrual anxiety.

Home-cage behavior is impacted by stress exposure in rats.

Being social animals, rats exhibit a range of social behaviors that help them build social bonds and maintain group cohesion. Behavior is influenced by multiple factors, including stress exposure, and the expression of the impact of stress on both social and non-social behaviors may also be affected by the living conditions of rats. In this study, we explored the physiological and behavioral effects of chronic unpredictable stress on group-housed rats in the PhenoWorld (PhW), a socially and physically enriched environment closer to real-life conditions. Two independent experiments were performed: one in the control condition (PhW control, n = 8) and one in the stress condition (PhW stress, n = 8). Control animals remained undisturbed except for cage cleaning and daily handling procedures. Stress group animals were all exposed to chronic unpredictable stress. Data confirm that stress exposure triggers anxiety-like behavior in the PhW. In terms of home-cage behaviors, we found that stress affects social behaviors (by decreased playing and increased huddling behaviors) and non-social behaviors (as shown by the decrease in rearing and walking behaviors). These results are of relevance to expand our knowledge on the influence of stress on social and non-social behaviors, which are of importance to understand better species-typical behaviors.

Chronic unpredictable stress changes left ventricular geometry and activation of the inflammasome

Background: Psychosocial stress, particularly chronic unpredictable stress (CUS) has been identified as a risk factor for cardiovascular disease, but the effects of CUS on left ventricle (LV) function, geometry and systemic hemodynamics remains unclear. Moreover, whether and to what degree CUS activates intracellular formation of the inflammasome, including the NOD-LRR pyrin containing protein 3 (NLRP3) remains unknown. Accordingly, the central hypothesis of this project was that in a murine model of CUS, shifts in LV geometry and systemic hemodynamics would occur and be associated with the induction of NLRP3. Methods and Results: Mice (C57BL/6, 10wks of age, equal sex, n=16) were subjected to CUS for 4 weeks which entailed daily random stressors including tilted cage, wet bedding, and overnight light. Referent age and sex matched non CUS mice served as controls (n=16). LV function was assessed by high fidelity ultrasound and blood pressure measurements by tail cuff for both referent control and CUS mice. The changes in ambient heart rate (HR), LV end-systolic volume (LVEDV), and systolic blood pressure (SBP) were expressed as a function of referent control. All results are reported as mean ± SEM. While LV ejection fraction was equivalent between CUS and control groups (70 ± 3 vs. 67 ± 3%, respectively, p=0.48), HR trended higher (4.5 ± 3.1%, p=0.08), LVEDV was lower (-11 ± 5%, p=0.03) and SBP was elevated (12.1 ± 4.9%, p=0.04) - all indicative of heightened sympathetic tone. LV myocardial NLRP3 (rtPCR) was increased (1.47 ± 0.22 fold change, p=0.04) with CUS as was IL-1β (1.43 ± 0.20 fold change, p=0.05), a downstream cytokine activated by NLRP3. Conclusion: CUS, in and of itself, shifts LV geometry, causes mild hypertension and induction of the myocardial inflammasome- all of which would exacerbate/contribute to cardiovascular disease. This work was supported in part by National Institutes of Health grant R01HL130972-01A1 (F.G.S.), R01HL5949 (F.G.S.), RO1DK132948 (C.W. &amp; F.P.), R01 MH129798 (SKW) and P20GM109091 (F.H.) as well as a Merit Award from the Veterans Health Administration, BX000168-10A1 (F.G.S.), BX005320 (F.G.S.), BX002604 (M.J.R.), and VISN7 RDA (F.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of chronic unpredictable stress on renal mitochondrial function in female mice

Background: Chronic stress can induce high blood pressure and lead to decreased renal function by mechanisms that remain unclear. The exposure of rodents to chronic unpredictable stress (CUS) is a translational model used for investigating the physiological impact of stress. The CUS protocol consists of unpredictable and random stressors that mimic real life exposure to stress. While stress is known to impact mitochondrial function, little is understood about the direct impact of chronic stress on renal mitochondrial respiration. Moreover, while studies have shown a link between estrogen and mitochondria through estrogen receptors, the relation between stress induced renal mitochondrial dysfunction and estrous cycle is unknown. Hypothesis: Exposing female mice to CUS will increase blood pressure and cause decreased renal mitochondrial respiration. Methods: We exposed adult female C57BL/6 mice to CUS for 28 days. Before and after stress, all control (CON, n=8) and CUS (n=10) mice were placed in metabolic cages for overnight urine collection. Urine albumin was measured by dipstick assay. On day 28, mice were assessed for blood pressure measurement via tail cuff. 24 hours later, mice were euthanized, and vaginal lavage was performed. The left kidney was removed, transected into thirds, and the poles were placed in relaxing buffer. Kidney mitochondrial oxygen consumption was assessed using high-resolution respirometry. Results: Data were stratified by phases of the estrus cycle. Neither blood pressure nor urinary albumin was significantly altered by CUS in stressed females. Females in estrus and proestrus exposed to CUS (n=5) exhibited a decrease of 20.8% ± 5.1 (n=5, p=0.03) in renal mitochondrial maximal uncoupled respiration compared to non-stressed CON. Renal mitochondrial respiration in diestrus was similar between CUS and CON. Conclusion: Results from this study reveal a link between the female estrus cycle, stress, and mitochondrial function. This work was supported by NIH grants P20GM109091 (F.H.), R01HL130972-01A1 (F.G.S.), R01HL5949 (F.G.S.), RO1DK132948 (C.W. &amp; F.P.) and R01 MH129798 (SKW); VA grants: VISN7 RDA (F.H.), Merit awards: BX000168-10A1 (F.G.S.), BX005320 (F.G.S.), and BX002604 (M.J.R.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis

Background: Stress is a real or perceived threat that elicits physiological and behavioral responses via activation of innate response mechanisms like the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS). Mitochondria are dynamic organelles responsible for providing cellular energy and the synthesis and release of glucocorticoids from the adrenal glands in response to stress. Thus, mitochondria represent the first line of response to environmental challenges, however, the effects of chronic stress on mitochondrial function in the HPA axis, particularly with respect to sex differences, are relatively unexplored. Hypothesis: Chronic unpredictable stress (CUS) induces mitochondrial dysfunction in key brain regions within the HPA axis.Methods: Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (CON) with weekly weighing. During the last week of stress, anxiety-like behavior was evaluated using the elevated plus maze and open field tests and coping behavior was assessed using the forced swim test. Mice were euthanized and the brain and adrenal glands dissected, weighed, and mitochondrial function was assessed using high resolution respirometry in hypothalamus, amygdala, and adrenal tissues. Results: CUS exposure decreased total body weight gain by 53% (p=0.04) and increased anxiety-like behavior (p=0.01) in stressed males compared to controls but had no effect on female weight or anxiety-like behavior. Stressed males and females both exhibited 46% decreased latency to immobility in the forced swim test (p=0.0001). CUS induced significant sex-dependent decreases in mitochondrial respiration within key stress centers, with stressed males exhibiting decreased respiration in the amygdala (20%, p=0.05), and stressed females exhibiting decreased respiration in the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06). Co nclusions: The unique findings of this study identified sex dependent CUS effects on HPA axis mitochondrial function. These observations suggest targeting mitochondria as a therapeutic strategy against stress-related pathologies. This work was supported by a NIH grants P20GM109091 (F.H.), R01HL130972-01A1 (F.G.S.), R01HL5949 (F.G.S.), RO1DK132948 (C.W. &amp; F.P.) and R01 MH129798 (SKW); VA grants: VISN7 RDA (F.H.), Merit awards: BX000168-10A1 (F.G.S.), BX005320 (F.G.S.), &amp; BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Depletion of microglial BDNF increases susceptibility to the behavioral and synaptic effects of chronic unpredictable stress

In the medial prefrontal cortex (PFC), chronic stress reduces synaptic expression of glutamate receptors, leading to decreased excitatory signaling from layer V pyramidal neurons and working memory deficits. One key element driving these changes is a reduction in brain-derived neurotrophic factor (BDNF) signaling. BDNF is a potent mediator of synaptic growth and deficient BDNF signaling has been linked to stress susceptibility. Prior studies indicated that neurons are the primary source of BDNF, but more recent work suggests that microglia are also an important source of BDNF. Adding to this, our work showed that 14 days of chronic unpredictable stress (CUS) reduced Bdnf transcript in PFC microglia, evincing its relevance in the effects of stress. To explore this further, we utilized transgenic mice with microglia-specific depletion of BDNF (Cx3cr1Cre/+:Bdnffl/fl) and genotype controls (Cx3cr1Cre/+:Bdnf+/+). In the following experiments, mice were exposed to a shortened CUS paradigm (7 days) to determine if microglial Bdnf depletion promotes stress susceptibility. Analyses of PFC microglia revealed that Cx3cr1Cre/+:Bdnffl/fl mice had shifts in phenotypic markers and gene expression. In a separate cohort, synaptoneurosomes were collected from the PFC and western blotting was performed for synaptic markers. These experiments showed that Cx3cr1Cre/+:Bdnffl/fl mice had baseline deficits in GluN2B, and that 7 days of CUS additionally reduced GluN2A levels in Cx3cr1Cre/+:Bdnffl/fl mice, but not genotype controls. Behavioral and cognitive testing showed that this coincided with exacerbated stress effects on temporal object recognition in Cx3cr1Cre/+:Bdnffl/fl mice. These results indicate that microglial BDNF promotes glutamate receptor expression in the PFC. As such, mice with deficient microglial BDNF had increased susceptibility to the behavioral and cognitive consequences of stress.

Effect of chronic unpredictable stress on behavioral analysis and cognitive functions in association with hippocampus glial cells

Exposure to different types of stress is one of the significant risk factors in the emergence of clinically diagnosable depression. Studies are considerably less correlating the effect of stress on glial cell astrocytes, cognitive functions and behavioral analysis. The present study was aimed to. correlate the effect of chronic unpredictable stress on astrocytes in the hippocampus, cognitive functions and behavioral analysis. Adult Wistar albino rats were divided into Control group and stressed group (n=6 in each group). The rat were exposed to chronic unpredictable stressors for 15 consecutive days. On 15th day, the cognitive functions and the behavioral analysis was done. The animals were anesthetized and hippocampus was dissected and the astrocyte count was done using immunostaining method. The astrocyte count significantly (p&lt;0.0001) decreased in the hippocampal tissue in the stressed group of rats. Moreover the decrease in the astrocytes was well associated with the significant decrease in the cognitive functions (p&lt;0.0001) and behavioral analysis(p&lt;0.0001). The current study focuses attention towards the strategies mitigating stress-induced cognitive dysfunction and altered behavioral responses associating astrocyte count targeting hippocampus. Reconsolidating pre-stress glial structure might prove therapeutically effective.

Investigating the role of environmental enrichment initiated in adolescence against the detrimental effects of chronic unpredictable stress in adulthood: Sex-specific differences in behavioral and neuroendocrinological findings

Environmental Enrichment (EE) improves cognitive function and enhances brain plasticity, while chronic stress increases emotionality, impairs learning and memory, and has adverse effects on brain anatomy and biochemistry. We explored the beneficial role of environmental enrichment initiated in adolescence against the negative outcomes of Chronic Unpredictable Stress (CUS) during adulthood on emotional behavior, cognitive function, as well as somatic and neuroendocrine markers in both sexes. Adolescent Wistar rats housed either in enriched or standard housing conditions for 10 weeks. On postnatal day 66, a subgroup from each housing condition was daily exposed to a 4-week stress protocol. Following stress, adult rats underwent behavioral testing to evaluate anxiety, exploration/locomotor activity, depressive-like behavior and spatial learning/memory. Upon completion of behavioral testing, animals were exposed to a 10-m stressful event to test the neuroendocrine response to acute stress. CUS decreased body weight gain and increased adrenal weight. Some stress-induced behavioral adverse effects were sex-specific since learning impairments were limited to males while depressive-like behavior to females. EE housing protected against CUS-related behavioral deficits and body weight loss. Exposure to CUS affected the neuroendocrine response of males to acute stress as revealed by the increased corticosterone levels. Our findings highlight the significant role of EE in adolescence as a protective factor against the negative effects of stress and underline the importance of inclusion of both sexes in animal studies.

Effect of chronic unpredictable stress on the chemopreventive potential of Quercetin in experimental carcinogenesis

Effect of chronic unpredictable stress on the chemopreventive potential of Quercetin in experimental carcinogenesis

Effect of chronic unpredictable stress on the progression of experimental apical periodontitis in rats.

To establish an experimental model combining chronic stress and apical periodontitis by assessing the development of periapical lesions in rats in three different time points. Forty-eight male Wistar rats were randomly assigned into two equal groups: Apical periodontitis (AP) and AP+Stress (AP+S). The animals of the AP group were not exposed to stressful conditions whereas the AP+S group were exposed to a variety of stressors on a daily basis until the end of the experiment. After three weeks of chronic unpredictable stress, apical periodontitis was induced in both groups by exposing the pulpal tissue of the mandibular first molar to the oral environment. Each group was further subdivided into three subgroups according to the euthanasia period: 14, 21 and 28days after pulp exposure. The animals were weighed, and the blood was collected for corticosterone serum dosage by radioimmunoassay. The mandibles were removed and submitted to histopathological and microtomography analyses to assess the inflammatory response and the progression of periapical lesions. Comparisons between the AP and AP+S groups were performed using Student's t-test and Mann-Whitney U-test for parametric and nonparametric data, respectively. The one-way anova test followed by Tukey's test (parametric data) and Kruskal-Wallis followed by Dunn's test (nonparametric data) were used for comparisons between the three time points within the same group (P<0.05). The AP+S group had a significantly lower average percentage of weight gain at 14days and 21days after AP induction (P<0.05). Significantly higher levels of corticosterone were found in the AP+S group at 21days (P<0.05). The AP+S group had a significantly greater intensity and extension of inflammatory infiltrate with larger areas of bone loss compared to the AP groups at 21days (P<0.05). The volume of the periapical lesions in the AP+S group was significantly larger than that of the AP group 21days following pulp exposure (P<0.05). The chronic unpredictable stress model applied for 6weeks exacerbated the inflammatory response and increased bone loss associated with AP, especially 21days after its induction. This model appears to be suitable for investigating the bidirectional relationship between apical periodontitis and chronic stress.

DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

Abstract Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

Telencephalon transcriptome analysis of chronically stressed adult zebrafish

Chronic stress leads to disruptions in learning and memory processes. The effects of chronic stress experience on the adult zebrafish brain, particularly the memory associated telencephalon brain region, is unclear. The goal of this study was to identify gene expression changes in the adult zebrafish brain triggered by chronic unpredictable stress. Transcriptome analysis of the telencephalon revealed 155 differentially expressed genes. Of these genes, some are critical genes involved in learning and memory, such as cdk5 and chrna7, indicating effects of chronic unpredictable stress on zebrafish memory. Interestingly, several genes were annotated in the Orange domain, which is an amino acid sequence present in eukaryotic DNA-binding transcription repressors. Furthermore, we identified hsd11b2, a cortisol inactivating gene, as chronic stress-responsive in the whole zebrafish brain. Collectively, these findings suggest that memory associated gene expression changes in adult zebrafish telencephalon are affected by chronic stress experience.

The Effects of Chronic Unpredictable Stress on Aorta Structure and Blood Lipids in Young and Old Rats

Objectives: Chronic stress can induce dyslipidemia that promotes atherosclerosis. The aim of this study was to assess the effects of chronic unpredictable stress (CUS) on aorta structure and blood lipids as well as body weight in young and old rats. Methods: Young and old rats were treated with chronic unpredictable stress (for eight weeks) to evaluate plasma lipids and aorta structure. Thickness and internal diameter of aortic tissue were assessed by the ImageJ software. Results: Stress decreased body weight gain in young rats (P < 0.05). Triglyceride, low density lipoprotein (LDL), very low density lipoprotein (VLDL) levels and low density lipoprotein/high density lipoprotein (LDL/HDL) ratio were more in old rats than young rats (P < 0.05). Stress significantly decreased serum triglyceride level in old rats (P < 0.05). Stress significantly increased VLDL level in young (10.3 ± 1.3 mg/dL versus 16.4 ± 2.1 mg/dL) and decreased VLDL level in old (10.8 ± 0.8 mg/dL versus 17.6 ± 1.6 mg/dL) rats (P < 0.05). The inner diameter of aorta was smaller in old (34.5 ± 1.7 micrometers) than young (42.3 ± 1.2 micrometers) rats (P < 0.01). Stress significantly increased inner diameter of aorta in old (42.3 ± 2.1 micrometers versus 34.5 ± 1.7 micrometers) rats (P < 0.01). Aortic wall thickness/aortic inner diameter ratio (AWT/AID) was greater in old rats than young rats. Conclusions: It seems that CUS has a dual effect on serum lipids and aortic diameter in young and old rats.

Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

The Abelson helper integration site 1 (Ahi1) gene plays a pivotal role in brain development and is associated with genetic susceptibility to schizophrenia, and other neuropsychiatric disorders. Translational research in genetically modified mice may reveal the neurobiological mechanisms of such associations. Previous studies of mice heterozygous for Ahi1 knockout (Ahi1+/−) revealed an attenuated anxiety response on various relevant paradigms, in the context of a normal glucocorticoid response to caffeine and pentylenetetrazole. Resting-state fMRI showed decreased amygdalar connectivity with various limbic brain regions and altered network topology. However, it was not clear from previous studies whether stress-hyporesponsiveness reflected resilience or, conversely, a cognitive-emotional deficit. The present studies were designed to investigate the response of Ahi1+/− mice to chronic unpredictable stress (CUS) applied over 9 weeks. Wild type (Ahi1+/+) mice were significantly affected by CUS, manifesting decreased sucrose preference (p < 0.05); reduced anxiety on the elevated plus maze and light dark box and decreased thigmotaxis in the open field (p < 0.01 0.05); decreased hyperthermic response to acute stress (p < 0.05); attenuated contextual fear conditioning (p < 0.01) and increased neurogenesis (p < 0.05). In contrast, Ahi1+/− mice were indifferent to the effects of CUS assessed with the same parameters. Our findings suggest that Ahi1 under-expression during neurodevelopment, as manifested by Ahi1+/− mice, renders these mice stress hyporesponsive. Ahi1 deficiency during development may attenuate the perception and/or integration of environmental stressors as a result of impaired corticolimbic connectivity or aberrant functional wiring. These neural mechanisms may provide initial clues as to the role Ahi1 in schizophrenia and other neuropsychiatric disorders.

Chronic Stress Alters Behavior in the Forced Swim Test and Underlying Neural Activity in Animals Exposed to Alcohol Prenatally: Sex- and Time-Dependent Effects.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress response has been suggested to play a role in vulnerability to stress-related disorders, such as depression. Prenatal alcohol exposure (PAE) may result in HPA dysregulation, which in turn may predispose individuals to the effects of stress exposure throughout life, and increase their risk of developing depression compared to unexposed individuals. We examined the immediate and delayed effects of chronic unpredictable stress (CUS) in adulthood on behavior of PAE animals in the forced swim test (FST) and the neurocircuitry underlying behavioral, emotional, and stress regulation. Adult male and female offspring from PAE and control conditions were tested for 2 days in the FST, with testing initiated either 1 day (CUS-1; immediate) or 14 days (CUS-14; delayed) post-CUS. Following testing, c-fos mRNA expression of the medial prefrontal cortex (mPFC), amygdala, hippocampal formation, and the paraventricular nucleus of the hypothalamus was assessed. Our results indicate that PAE and CUS interact to differentially alter FST behaviors and neural activation of several brain areas in males and females, and effects may depend on whether testing is immediate or delayed post-CUS. PAE males showed decreased time immobile (Day 1 of FST) following immediate testing, while PAE females showed increased time immobile (Day 2 of FST) following delayed testing compared to their respective control counterparts. Moreover, in males, PAE decreased c-fos mRNA expression in the lateral and central nuclei of the amygdala in the non-CUS condition, and increased c-fos mRNA expression in the CA1 in the CUS-14 condition. By contrast in females, c-fos mRNA expression in the Cg1 was decreased in PAE animals (independent of CUS) and decreased in all mPFC subregions in CUS-14 animals (independent of prenatal treatment). Constrained principal component analysis, used to identify neural and behavioral networks, revealed that PAE altered the activation of these networks and modulated the effects of CUS on these networks in a sex- and time-dependent manner. This dysregulation of the neurocircuitry underlying behavioral, emotional and stress regulation, may ultimately contribute to an increased vulnerability to psychopathologies, such as depression, that are often observed following PAE.

CHRONIC UNPREDICTABLE STRESS-INDUCED BEHAVIORAL AND ELECTROPHYSIOLOGICAL ALTERATIONS AND ITS AMELIORATIVE EFFECT BY MYRICETIN MICROEMULSION

Objective: The present study is designed to investigate the effects of chronic unpredictable stress (CUS) on electrophysiological and behavioral alterations in male Wistar albino rats and its ameliorating effect by myricetin-microemulsion (MYR-ME).Materials and Methods: Adult Wistar male albino rats were exposed to CUS for 21 days and treated with MYR-ME (10 mg/kg) for 21 days by oral administration. All the experimental animals were tested for anxiety and cognitive behavior by open-field behavior, light/dark test, eight-arm radial maze, spontaneous alteration T-maze, novel object recognition test, plasma corticosterone level, and electrophysiological activity.Results: The rats which were exposed to CUS showed memory impairment, increased anxiety, decreased novel explorations, deleterious effect on decision-making, increased corticosterone level, increased brain wave frequency and amplitude, and also heart rate. Whereas, CUS with MYR-ME-treated group showed a protective effect against CUS-induced behavioral alterations, electrophysiological activity, and corticosterone levels, which is characterized by the enhancement of cognitive function, decreased anxiety and improved decision-making, novel exploration, decreased corticosterone, and electrophysiological activity.Conclusion: From the present study, it is shown that MYR-ME may act as a potential anxiolytic and nootropic compound against CUS-induced alterations.

Rough-and-tumble play induces resilience to stress in rats.

Positive emotions have been shown to induce resilience to stress in humans, as well as increase cognitive abilities (learning, memory, and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic vocalizations (hedonic 50 kHz) reflect a positive affective state and are best elicited by rough-and-tumble play. A well-established rat chronic unpredictable stress paradigm was used to produce a robust and long-lasting decrease in positive affect, increase in negative affect, and learned helplessness in Sprague-Dawley rats. Rough-and-tumble play (3 min every 3 days) reversed stress-induced effects of chronic unpredictable stress in the Porsolt forced swim test, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays compared with a light touch control group. These data demonstrate that positive affect induces resilience to stress effects in rats, and that rough-and-tumble play can be used to explore the biological basis of resilience that may lead to the development of new therapeutics for stress-related disorders.

Up-regulation of GluR1 in paraventricular nucleus and greater expressions of synapse related proteins in the hypothalamus of chronic unpredictable stress-induced depressive rats

Converging evidence indicates that abnormal glutamatergic and synaptic systems may be associated with the pathophysiology of depression. Over-activation of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) plays a key role in the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and is a prominent feature in depression. In this study, we examined the effect of chronic unpredictable stress (CUS) in rats on the expression of AMPA subunit GluR1 protein in the hypothalamic PVN as well as on the expression of GluR1 and several synapse-related proteins in the hypothalamus. We found that CUS in rats induced CRH over-expression accompanied by significant GluR1 up-regulation in the hypothalamic PVN and GluR1 co-localized with CRH in the PVN area. The expression of GluR1 and three synapse-related proteins (PSD95, SYP and MAP2) in the hypothalamus were also increased at both mRNA and protein levels in CUS rats. Correlation analysis showed that the levels of the above proteins are directly correlated with depression-like behaviors of rats in sucrose preference test, open field test and forced swim test. These findings suggest that the augmented glutamatergic and synaptic signaling might be a potential mechanism underlying CRH over-activation in the hypothalamic PVN and contribute to CUS-induced depression-like behaviors in rats.