Stress-induced Increases In Corticosterone Research Articles

Acute and chronic cannabis vapor exposure influences basal and stress-induced release of glucocorticoids in male and female rats.

Management of stress and anxiety is often listed as the primary motivation behind cannabis use. Human research has found that chronic cannabis use is associated with increased basal cortisol levels but blunted neuroendocrine responses to stress. Preclinical research has demonstrated mixed effects of Δ9-tetrahydrocannabinol (THC; the psychoactive constituent of cannabis), much of which is suggestive of dose-dependent effects; however, the predominance of this work has employed an injection method to deliver cannabis. As inhalation is the most common route of administration in humans, we employed a translationally relevant model of inhaled cannabis vapor exposure to help characterize the extent to which acute and chronic cannabis exposure modulates neuroendocrine responses to stress. Male and female Sprague-Dawley rats were acutely (single day) or chronically (10 days) exposed to cannabis or vehicle vapor, and the stress hormone, corticosterone, was analyzed prior to and following an acute 30-min restraint stress. Our results indicate that initial exposure to the vapor chambers, regardless of vehicle or cannabis exposure, is sufficient to elevate corticosterone levels in male and female rodents. Further, acute cannabis exposure was capable of increasing corticosterone levels in both male and female rats, however, this effect was modified by the habituation to the vapor chambers differentially in males and females. Regardless of sex, chronic cannabis exposure is sufficient to both elevate basal corticosterone levels and blunt stress-induced increases in corticosterone following a restraint stressor. Collectively, these data help characterize the impacts of cannabis vapor exposure on basal and stress-induced activation of the hypothalamic-pituitary-adrenal axis.

Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder

Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T+ Itpr3tf/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6Chi monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.

Exercise before pregnancy attenuates the effects of prenatal stress in adult mice in a sex-dependent manner.

The present study aimed to investigate the long-term effects of exercise before pregnancy on changes induced by prenatal stress. Female and male Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX+PNS). As adult, fear/anxiety behavior, corticosterone secretion, expression of hypothalamic-pituitary-adrenal (HPA)-related genes, as well as epigenetic modifications were evaluated. Exercise before gestation did not prevent the increased fear/anxiety behavior in PNS mice. A nearly significant (p=.06) basal corticosterone increase was observed in PNS males and the exercise before pregnancy reduced the stress-induced corticosterone increase in PNS females. In addition, an increase on prefrontal cortex (PFC) CRHR1 gene expression was observed in PNS females, which was attenuated by the exercise before gestation. We have also found a glucocorticoid receptor(GR) gene expression decrease in the prefrontal cortex in PNS males, as well as a histone H3 acetylation decrease (p=.06) close to the significance level. In conclusion, pregestational exercise may attenuate developmental changes induced by prenatal stress in a sex-dependent manner.

Oral Administration of Rauwolfia Serpentina Plant Extract Mitigated Immobilization Stress-Induced Biochemical and Behavioral Deficits in Rats

Rauwolfia Serpentina is a medicinal herb used for hypertension and psychotic disorders. In this study neuroprotective effects of Rauwolfia serpentina plant extract following the exposure to acute immobilization (2h) stress in rats were investigated. The extract of the plant administered orally at non-sedative dose 30mg/kg before immobilization (2h) to observe stress induced behavioral deficits. Neuroprotective efficacy of extract was assessed in terms of alteration in activities of antioxidant enzymes like superoxide dismutase (SOD) and catalase (CAT). We also monitored leptin, corticosterone and glucose levels in plasma to obtain an imminent role of Rauwolfia serpentina. Animals were orally administered with Rauwolfia serpentina (30mg/kg) while controls receive saline (1ml/kg). Each group was subdivided into stressed and unstressed groups. Behavioral deficits were monitored in the open field and light dark activity box. Animals were decapitated; plasma samples were collected for CAT, SOD, corticosterone, leptin and glucose estimation. Orally administered Rauwolfia serpentina attenuates stress induced behavioral deficits and rise antioxidant enzymes levels. Plant extract also prevents the stress-induced increase in corticosterone but glucose levels do not manifest any significant change. Immobilization stress (2h) induced decrease of plasma leptin levels were reversed by Rauwolfia serpentina. Therefore, the present study suggests that Rauwolfia serpentina has potentiality to antagonize undesirable effects of immobilization stress (2h) by reducing stress perception and inhibitory effects of stress on the activity of hypothalamic pituitary adrenal (HPA) axis and animal behaviors. Despite an apparent role of Rauwolfia serpentina the mechanism of action at molecular level causing the acute anxiolytic effects of oral administration of plant extract remains to be determined.

Oral Administration of Rauwolfia Serpentina Plant Extract Mitigated Immobilization Stress-Induced Biochemical and Behavioral Deficits in Rats

Rauwolfia Serpentina is a medicinal herb used for hypertension and psychotic disorders. In this study neuroprotective effects of Rauwolfia serpentina plant extract following the exposure to acute immobilization (2h) stress in rats were investigated. The extract of the plant administered orally at non-sedative dose 30mg/kg before immobilization (2h) to observe stress induced behavioral deficits. Neuroprotective efficacy of extract was assessed in terms of alteration in activities of antioxidant enzymes like superoxide dismutase (SOD) and catalase (CAT). We also monitored leptin, corticosterone and glucose levels in plasma to obtain an imminent role of Rauwolfia serpentina. Animals were orally administered with Rauwolfia serpentina (30mg/kg) while controls receive saline (1ml/kg). Each group was subdivided into stressed and unstressed groups. Behavioral deficits were monitored in the open field and light dark activity box. Animals were decapitated; plasma samples were collected for CAT, SOD, corticosterone, leptin and glucose estimation. Orally administered Rauwolfia serpentina attenuates stress induced behavioral deficits and rise antioxidant enzymes levels. Plant extract also prevents the stress-induced increase in corticosterone but glucose levels do not manifest any significant change. Immobilization stress (2h) induced decrease of plasma leptin levels were reversed by Rauwolfia serpentina. Therefore, the present study suggests that Rauwolfia serpentina has potentiality to antagonize undesirable effects of immobilization stress (2h) by reducing stress perception and inhibitory effects of stress on the activity of hypothalamic pituitary adrenal (HPA) axis and animal behaviors. Despite an apparent role of Rauwolfia serpentina the mechanism of action at molecular level causing the acute anxiolytic effects of oral administration of plant extract remains to be determined.

Differential effects of high-fat diet on glucose tolerance, food intake, and glucocorticoid regulation in male C57BL/6J and BALB/cJ mice

The C57BL/6J strain of laboratory mice is a popular subject for studies of diet-induced obesity and diabetes given its propensity for developing obesity and glucose intolerance when placed on high-fat diet. High-fat diet leads to much lower weight gain in young adult BALB/cJ mice, which appear to be protected from many of the metabolic effects of high-fat diet observed in C57BL/6J mice. In this report, the effects of diet and timing of feeding on body weight, food intake, glucose tolerance, and stress-induced corticosterone and blood glucose responses were assessed in male C57BL/6J and BALB/cJ mice. Lower glucose tolerance was observed in low-fat diet-fed C57BL/6J than BALB/cJ mice at four times sampled across the circadian cycle. Ad libitum high-fat diet increased the amount of daytime eating behavior and led to impaired glucose regulation in C57BL/6J but not BALB/cJ mice. Restricting food availability to either daytime or nighttime did not prevent overall body weight gain, but restricting feeding to nighttime (but not daytime) did prevent the significant increase in perigonadal fat pad mass produced by high-fat diet in C57BL/6J mice. Baseline corticosterone levels at their typical daily peak near onset of daily activity were blunted in both strains of mice after 8 weeks on high-fat diet, without corresponding differences in baseline glucose levels. Restraint stress-induced increases in corticosterone were exaggerated in C57BL/6J mice on high-fat diet, with concomitant increases in blood glucose. Paradoxically, stress-induced corticosterone responses were even more exaggerated in BALB/cJ mice yet with significantly blunted glucose responses compared to C57BL/6J mice, regardless of diet, indicating that corticosterone does not have equivalent glucogenic effects in young adult male BALB/cJ and C57BL/6J mice on high-fat diet. These results document considerable strain differences that may provide means for elucidating the mechanisms involved in diet-induced obesity, while highlighting the need to consider these strain differences when extending the results of mouse studies toward the human condition.

Bstract # 3140 Gut microbial modulatory diets modulate stress-evoked sterile inflammation

Gut microbial modulatory (GMM) diets containing prebiotic nutrients favor the growth and metabolic function of health promoting gut bacteria and reduce the negative impacts of stressor exposure on mood, sleep, and gut microbial dysbiosis. Stressor exposure can increase inflammatory proteins in the absence of pathogens (sterile inflammation). This study tested the hypothesis that GMM diets modulate stress-evoked sterile inflammation. Male F344 rats were assigned either GMM diets or isocaloric-nutrient matched control diet. After 4 weeks, rats were exposed to stress (intermittent tailshock-90 min) or remained in their home cages. Immediately after stressor termination, rats were sacrificed and blood and tissues were collected. Consistent with previous results, GMM diets increased stress-protective gut bacteria (fecal L. rhamnosus). Although GMM diet minimally impacted stress-induced increases in corticosterone, glucose or splenic contraction (indicative of sympathetic drive), it did constrain sterile inflammation, most notably CINC-1/CXCL8 (plasma, spleen, mesenteric lymph nodes (MLN)) and IL6 (plasma). GMM diets also increased IL10 (MLN) and reduced the stress-evoked increase in tissue Hsp72 (MLN, liver) compared to control, indicative of reduced cellular stress. The mechanisms for how GMM diets broadly impact stress physiology including sterile inflammation are unknown. Recent evidence, however, suggests that metabolic signals fueled by prebiotic nutrients from gut microbes impact the brain, increasing cfosin vagal afferent termination sites (NTS) and dorsal raphe nucleus (DRN); and prevent stress-evoked downregulation of DRN 5HT1AR.

A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression.

Preclinical testing of treatments for postpartum depression (PPD) has been limited due to the lack of available animal models of such a complex disorder. To address this limitation, our laboratory has generated unique preclinical mouse models that exhibit abnormal postpartum behaviors. Mice with a loss or reduction in the expression of the GABAA receptor (GABAAR) δ subunit (Gabrd−/− or Gabrd+/−, respectively) and mice that lack the K+/Cl− co-transporter, KCC2, specifically in corticotropin-releasing hormone (CRH) neurons (KCC2/Crh mice) exhibit depression-like behaviors restricted to the postpartum period and deficits in maternal care, which serve as useful tools for testing novel therapeutic compounds. Utilizing these preclinical models, we tested the ability of a novel, synthetic, neuroactive steroid developed by SAGE Therapeutics, SGE-516, to improve abnormal postpartum behaviors. Gabrd−/−, Gabrd+/−, and KCC2/Crh dams treated with SGE-516 (450 mg/kg chow) during late pregnancy exhibit a decrease in depression-like behaviors and improvements in maternal care at 48 h postpartum. Interestingly, acute treatment with SGE-516 also exhibits robust therapeutic effects in these preclinical PPD models. We previously discovered abnormal stress reactivity associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with depression-like behaviors in the preclinical PPD models, evident from an increase in stress-induced corticosterone levels and dephosphorylation and downregulation of KCC2 in the paraventricular nucleus of the hypothalamus (PVN) during the peripartum period. Here we demonstrated that SGE-516 treatment is sufficient to prevent the stress-induced increase in corticosterone and dephosphorylation and downregulation of KCC2 in the PVN. In contrast, and consistent with the distinct pharmacology of SGE-516 compared to benzodiazepines, treatment with clobazam (250 mg/kg chow) did not alter the depression-like phenotype or deficits in maternal care observed in these preclinical models of PPD. These findings are consistent with the positive double-blind, randomized, placebo-controlled trial findings of a similar compound, brexanolone, in the treatment of patients with postpartum depression. Further, these findings validate the use of these preclinical models of PPD for screening novel compounds for the treatment of postpartum depression.

Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex

BackgroundClinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone “set the stage” for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL). MethodsWe have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons. ResultsCorticosterone application attenuated inhibitory synaptic transmission in the PL via cannabinoid receptor type 1 (CB1R)– and 2-arachidonoylglycerol–dependent inhibition of gamma-aminobutyric acid release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB1R agonist WIN 55,212-2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB1R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34. ConclusionsThese findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CB1R-mediated attenuation of inhibitory transmission in this brain region.

Highly palatable food access during adolescence increased anxiety-/depression-like behaviors in male, but not in female, rats

Objectives: This study was conducted to examine the sexual dimorphic effects of highly palatable food (HPF) access during adolescence on the neurochemistry and depression-/anxiety-like behaviors of rats.Methods: Male and female Sprague–Dawley pups had free access to chocolate cookie rich in fat (HPF) from postnatal day 28 in addition to ad libitum chow, and the control groups received only chow. The food conditions were continued throughout the entire experimental period, and the neurochemical and behavioral measurements were performed during young adulthood. Rats were subjected to the ambulatory activity, elevated plus maze, and forced swim tests. Corticosterone levels during 2 h of restraint stress were analyzed with radioimmunoassay, and ΔFosB and brain-derived neurotrophic factor (BDNF) expression in the nucleus accumbens (NAc) with Western blot analysis.Results: Cookie access did not affect body weight gain and total caloric intake in both sexes; however, it increased retroperitoneal fat depot only in males. The time spent in open arms during elevated plus maze test was decreased and immobility during forced swim test was increased in cookie-fed males, but not in cookie-fed females. Main effect of food condition on the stress-induced corticosterone increase was observed in males, but not in females, and cookie access increased BDNF expression in the NAc only in males.Conclusions: Increased BDNF expression in the NAc and fat depot, in addition to the stress axis dysfunction, may play roles in the pathophysiology of depression- and/or anxiety-like behaviors induced by cookie access.

Palatable food access during adolescence increased BDNF expression in the nucleus accumbens and anxiety-/depression-like behaviors in males, but not in females

ObjectivesThis study was conducted to examine sexual dimorphic effects of highly palatable food access during adolescence and youth on psychoemotional behaviors of rats and its underlying neural mechanism.MethodsMale and female Sprague Dawley pups had free access to chocolate cookie rich in fat (highly palatable food) from postnatal day 28 in addition to ad libitum chow, and the control groups received chow only. The food conditions were continued though out the entire experimental period, and the neurochemical and behavioral measurements were performed during young adulthood. Corticosterone levels during 2 h of restraint stress were analyzed with radioimmunoassay, and ΔFosB and brain-derived neurotrophic factor (BDNF) expression in the nucleus accumbens (NAc) with western blot analysis.ResultsCookie access did not affect body weight gain and total caloric intake in both sexes; however, it increased retroperitoneal fat depot only in males. The time spent in open arms during elevated plus maze test was decreased and immobility during forced swim test was increased in cookie-fed males, but not in cookie-fed females. Main effect of food condition on the stress-induced corticosterone increase was observed in males, but not in females, and cookie access increased BDNF expression in the NAc only in males.ConclusionsIncreased BDNF expression in the NAc and fat depot, in addition to the HPA axis dysfunction, may play roles in the pathophysiology of depression- and/or anxiety-like behaviors induced by cookie access.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Endocrine-reproductive-immune interactions in female and male Galápagos marine iguanas

Endocrine-immune interactions are variable across species and contexts making it difficult to discern consistent patterns. There is a paucity of data in non-model systems making these relationships even more nebulous, particularly in reptiles. In the present study, we have completed a more comprehensive test of the relationship among steroid hormones and ecologically relevant immune measures. We tested the relationship between baseline and stress-induced levels of sex and adrenal steroid hormones and standard ecoimmunological metrics in both female and male Galápagos marine iguanas (Amblyrhynchus cristatus). We found significant associations between adrenal activity and immunity, whereby females that mounted greater corticosterone responses to stress had lower basal and stress-induced immunity (i.e., bactericidal ability). Males showed the opposite relationship, suggesting sex-specific immunomodulatory actions of corticosterone. In both sexes, we observed a stress-induced increase in corticosterone, and in females a stress-induced increase in bactericidal ability. Consistent with other taxa, we also found that baseline corticosterone and testosterone in males was inversely related to baseline bactericidal ability. However, in females, we found a positive relationship between both testosterone and progesterone and bactericidal ability. Multivariate analysis did not discern any further endocrine-immune relationships, suggesting that interactions between adrenal, sex steroid hormones, and the immune system may not be direct and instead may be responding to other common stimuli, (i.e., reproductive status, energy). Taken together, these data illustrate significant endocrine-immune interactions that are highly dependent on sex and the stress state of the animal.

Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses

Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior.

Effects of Active Mastication on Chronic Stress-Induced Bone Loss in Mice.

Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a wooden stick to chew during the experimental period. Quantitative micro-computed tomography, histologic analysis, and biochemical markers were used to evaluate the bone response. The stress/chewing group exhibited significantly attenuated stress-induced increases in serum corticosterone levels, suppressed bone formation, enhanced bone resorption, and decreased trabecular bone mass in the vertebrae and distal femurs, compared with mice in the stress group. Active mastication during exposure to chronic stress alleviated chronic stress-induced bone density loss in B6 mice. Active mastication during chronic psychologic stress may thus be an effective strategy to prevent and/or treat chronic stress-related osteopenia.

Environmental enrichment and cafeteria diet attenuate the response to chronic variable stress in rats

Exposure to an enriched environment (EE) or the intake of a highly palatable diet may reduce the response to chronic stress in rodents. To further explore the relationships between EE, dietary intake and stress, male Sprague–Dawley rats were fed one of two diets for 5weeks: high carbohydrate (HC) or “cafeteria” (CAF) (Standard HC plus a choice of highly palatable cafeteria foods: chocolate, biscuits, and peanut butter). In addition, they were either housed in empty cages or cages with EE. 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. Rats were sacrificed at the end of the 5-week period. The effects of stress, enrichment and dietary intake on animal adiposity, serum lipids, and stress hormones were analyzed. Results showed an increase in intra-abdominal fat associated with the CAF diet and an increase in body weight gain associated with both the CAF diet and EE. Furthermore, the increase in ACTH associated with CVS was attenuated in the presence of EE and the CAF diet independently while the stress-induced increase in corticosterone was reduced by the combination of EE and CAF feeding. The present study provides evidence that the availability of a positive environment combined to a highly palatable diet increases resilience to the effects of CVS in rats. These results highlight the important place of palatable food and supportive environments in reducing central stress responses.

P.2.003 ATP as a regulator of anxiety-like behaviour in the paraventricular nucleus of rats

the pup retrieval test, maternal aggression in the maternal defense test, and anxiety-related behavior on the elevated plus-maze. In a different set of dams, we assessed HPA axis activation upon specific CRF-R manipulation under basal and stressful conditions via repeated blood sampling and measured adrenocorticotropic hormone (ACTH) and corticosterone levels. Maternal care was differentially changed by CRF-R subtype-specific manipulation. Arched back nursing (ABN; one-way ANOVA; F4,32 = 4.81, p< 0.01), indicative of nursing quality, was improved by the CRF-R1 antagonist but also the CRF-R2 agonist (p = 0.03, each). The occurrence of total nursing (F4,32 = 12.87, p< 0.01), indicative of nursing quantity, was reduced by both agonists (p< 0.01, each). These results demonstrate that the receptor subtypes antagonize maternal care in the adBNST in contrast to their cooperation in the pBNST. Following stressful conditions, i.e. after maternal defense, ABN tended to be improved only by the CRF-R1 antagonist (t-test vs. control; t13 = −1.99, p = 0.06). Maternal aggression, maternal motivation, and anxiety were not affected by any manipulation. Regarding the HPA axis, we found that under basal conditions ACTH release (repeated measures ANOVA; F7.7,156 = 9.2, p< 0.01) was increased by the CRF-R1 agonist only (p< 0.01) while corticosterone release (F15.2,186 = 2.7, p< 0.01) was increased by both agonists (p< 0.05, each). Under stressful conditions, corticosterone levels remained high in CRF-R1 agonist-treated dams while a switch was observed in CRF-R2 agonist-treated dams (p< 0.05, each). Both antagonists prevented the stress-induced increase in corticosterone (p< 0.05, each). These results indicate that intra-adBNST activation of both receptor subtypes activates the HPA axis under basal conditions whereas in stressful situations CRF-R1 and CRF-R2 act in an antagonizing manner. In conclusion, maternal behavior is differentially regulated by CRF-R1 and CRF-R2 depending on the site of activation within the BNST. Moreover, altered HPA axis activity might be involved in or even responsible for the observed changes in behavioral patterns. These data extend our basic understanding of the maternal brain and provide new insights into potential dysregulations postpartum.

Increased depression-like behaviors with dysfunctions in the stress axis and the reward center by free access to highly palatable food

This study was conducted to examine the behavioral consequences of unlimited consumption of highly palatable food (HPF) and investigate its underlying neural mechanisms. Male Sprague–Dawley rats had free access to chocolate cookie rich in fat (HPF) in addition to ad libitum chow and the control group received chow only. Rats were subjected to behavioral tests during the 2nd week of food condition; i.e. ambulatory activity test on the 8th, elevated plus maze test (EPM) on the 10th and forced swim test (FST) on the 14th day of food condition. After 8days of food condition, another group of rats were placed in a restraint box and tail bloods were collected at 0, 20, 60, and 120 time points during 2h of restraint period, used for the plasma corticosterone assay. At the end of restraint session, rats were sacrificed and the tissue sections of the nucleus accumbens (NAc) were processed for c-Fos immunohistochemistry. Ambulatory activities and the scores of EPM were not significantly affected by unlimited cookie consumption. However, immobility duration during FST was increased, and swim decreased, in the rats received free cookie access compared with control rats. Stress-induced corticosterone increase was exaggerated in cookie-fed rats, while the stress-induced c-Fos expression in the NAc was blunted, compared to control rats. Results suggest that free access to HPF may lead to the development of depression-like behaviors in rats, likely in relation with dysfunctions in the hypothalamic–pituitary–adrenal axis and the reward center.

Highly Palatable Food during Adolescence Improves Anxiety-Like Behaviors and Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Rats that Experienced Neonatal Maternal Separation.

BackgroundThis study was conducted to examine the effects of ad libitum consumption of highly palatable food (HPF) during adolescence on the adverse behavioral outcome of neonatal maternal separation.MethodsMale Sprague-Dawley pups were separated from dam for 3 hours daily during the first 2 weeks of birth (maternal separation, MS) or left undisturbed (nonhandled, NH). Half of MS pups received free access to chocolate cookies in addition to ad libitum chow from postnatal day 28 (MS+HPF). Pups were subjected to behavioral tests during young adulthood. The plasma corticosterone response to stress challenge was analyzed by radioimmunoassay.ResultsDaily caloric intake and body weight gain did not differ among the experimental groups. Ambulatory activities were decreased defecation activity and rostral grooming were increased in MS controls (fed with chow only) compared with NH rats. MS controls spent less time in open arms, and more time in closed arms during the elevated plus maze test, than NH rats. Immobility duration during the forced swim test was increased in MS controls compared with NH rats. Cookie access normalized the behavioral scores of ambulatory and defecation activities and grooming, but not the scores during the elevated plus maze and swim tests in MS rats. Stress-induced corticosterone increase was blunted in MS rats fed with chow only, and cookie access normalized it.ConclusionProlonged access to HPF during adolescence and youth partly improves anxiety-related, but not depressive, symptoms in rats that experienced neonatal maternal separation, possibly in relation with improved function of the hypothalamic-pituitary-adrenal (HPA) axis.

The differential role of NOS inhibitors on stress-induced anxiety and neuroendocrine alterations in the rat

The inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-properties in animal model. In order to examine the involvement of nitric oxide (NO) on stress-induced neurobehavioral changes and the concomitant alterations of neuroendocrinological factors, we studied the effects of the nonselective NOS inhibitor, Nω-Nitro l-arginine methyl ester hydrochloride (l-NAME) and the specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) on restraint stress-induced anxiety in the elevated plus maze (EPM) test and biochemical analysis. Restraint stress significantly reduced the latency time in open arm and the percentage of open arm entries of the plus maze. Pretreatment with l-NAME (10mg/kg) or 7-NI (10mg/kg) significantly attenuated stress-induced anxiety response. In addition, administration of l-NAME (10mg/kg) reversed stress-induced increase in corticosterone and NO metabolites (NOx) in plasma. The administration of 7-NI, but notl-NAME, reversed stress-induced NOx in paraventricular nucleus of the hypothalamus (PVN) and locus coeruleus (LC), accompanying with decrease of NADPH-d reactivity in the PVN and lateral dorsal tegmental nucleus (LTDg). These results showed that l-NAME influences HPA axis activity such as corticosterone levels and NOx in plasma, whereas 7-NI produced anxiolytic-like effects through the direct reduction in NOx in the brain. The results of this study demonstrated that NOS inhibitors have differential effect on stress responses and inhibition of NO could be responsible for the beneficial effect on regulation of stress.

The response of neuregulin 1 mutant mice to acute restraint stress

Stress plays a role in the development and severity of psychotic symptoms and there may be a genetic component to stress vulnerability in schizophrenia. Using an established mouse model for schizophrenia, we investigated the behavioural and endocrine response of Nrg1 transmembrane domain mutant mice (Nrg1 HET) and wild type-like (WT) littermates to acute restraint stress. Animals were screened at 3–4 months and 6–7 months of age (before and after onset of hyperlocomotion) for open field behaviour and serum corticosterone levels. In younger mice, stress reduced locomotive and explorative measures and increased anxiety-like behaviour regardless of genotype. Older Nrg1 mutants were less susceptible to the effects of stress on anxiety-related behaviours. All mice responded to restraint stress with robust increases in serum corticosterone. Importantly, the stress-induced increase in corticosterone was more pronounced in Nrg1 mutant than WT mice at the younger but not the older age. Our results suggest that transmembrane domain Nrg1 has only a moderate effect on the acute stress response of mice. The behavioural differences detected between WT and Nrg1 HET mice at the older age were evident without parallel modifications to the glucocorticoid system.