Changes In Plasma Corticosterone Research Articles

Circadian rhythm shifts and alcohol access in adolescence synergistically increase alcohol preference and intake in adulthood in male C57BL/6 mice

BackgroundAdolescents have a natural tendency to be night owls, maintaining delayed circadian rhythms, and this rhythm is in direct conflict with the early wake times required during the school year. This leads to ‘social jetlag’, chronic circadian stress or desynchrony (CD) in which the rhythm of the intrinsic body clock is out of sync with behavior. CD increases alcohol intake in adolescents and adults, yet it is unknown whether adolescent CD also increases long-term addiction risk. The goal of this study was to determine whether adolescent alcohol intake in CD would increase adult alcohol preference and intake in male C57BL/6 J mice. Methods: We measured free access alcohol intake, water intake, and wheel-running activity during a normal 12 h (h) baseline photoperiod and then during shifting lighting schedules (Experiment 1) or a shortened circadian day (Experiment 2). Results: In Experiment 1, altered lighting produced a persistent increase in adolescent alcohol intake and in binge-like drinking (drinking at least 5 licks per minute, with no more than a 1 min break in drinking) in adulthood, but only a transient increase in total alcohol intake for the first week after alcohol was reintroduced in adulthood. In Experiment 2, the circadian shift produced a significant increase in alcohol intake in both adolescence and adulthood. Molecular analysis demonstrated changes in plasma corticosterone and neuronal markers of stress and addiction at the conclusion of these experiments in the CD and alcohol-exposed groups. Conclusions: Thus, we conclude that circadian stress during adolescence is sufficient to produce a long-lasting susceptibility to alcohol use.

The Impact of Sex on Changes in Plasma Corticosterone and Cotinine Levels Induced by Nicotine in C57BL/6J Mice.

We assessed if there were any sex-related differences in the ability of nicotine to increase plasma corticosterone secretion after single or repeated nicotine administration. For single-dose studies, male and female mice were habituated to the test room for 1 h and injected with saline or nicotine (0.25 or 1 mg/kg, subcutaneously (s.c.)). In repeated-dosing studies, mice were injected with saline or nicotine (1 mg/kg, s.c.) once daily for six days, and, on day 7, received nicotine (1 mg/kg, s.c.). Mice were then euthanized 15 min later, and trunk blood was collected for the measurement of corticosterone, nicotine, and cotinine. Our results showed that saline or nicotine each significantly increased plasma corticosterone levels in both males and females, with a greater response in female mice. Plasma corticosterone levels were increased in male but not female mice after being treated repeatedly compared to single nicotine administration. The level of cotinine, a biomarker of nicotine use, was significantly higher in female than in male mice. Taken together, these novel findings suggest that female mice respond to nicotine and the stress of handling more than male mice and provide for the first-time quantitative data on male–female differences in nicotine-induced elevations of corticosterone and cotinine plasma levels.

Glucocorticoids, energy metabolites, and immunity vary across allostatic states for plateau side-blotched lizards (Uta stansburiana uniformis) residing in a heterogeneous thermal environment.

Reptiles rely on thermal heat exchange to achieve body temperatures (Tbody ) conducive to maintaining homeostasis. Diurnal changes in the thermal environment are therefore liable to influence allostatic mediation of survival processes (e.g., immunity) during environmental challenges or stressors. However, the extent to which Tbody prompts individual variation in physiology remains largely unexplored in reptiles. Our study tested how circulating energy-mobilizing hormone, energy metabolites, and immunity can vary across basal and stress-induced allostatic states for plateau side-blotched lizards (Uta stansburiana uniformis) residing in a heterogeneous thermal environment. We collected baseline and acute stress blood samples from male lizards to compare changes in plasma corticosterone (CORT), glucose, and bacterial killing ability (BKA) in relation to each other and Tbody . We hypothesized each physiological parameter differs between allostatic states, whereby stress-induced activity increases from baseline. At basal and stress-induced states, we also hypothesized circulating CORT, glucose, and BKA directly correspond with each other and Tbody . We found both CORT and BKA increased while glucose instead decreased from acute stress. At basal and stress-induced allostatic states, we found CORT to be directly related to Tbody while BKA was inversely related to CORT. We also found BKA and glucose were directly related at baseline, but inversely related following acute stress. Overall, these results demonstrate allostatic outcomes from acute stress in a free-living reptile and the role of temperature in mediating energetic state and immunity. Future research on reptilian allostasis should consider multiple environmental conditions and their implications for physiological performance and survival.

Foraging tactics in dynamic sea‐ice habitats affect individual state in a long‐ranging seabird

Abstract Individual heterogeneity in diet and foraging behaviour is common in wild animal populations, and can be a strong determinant of how populations respond to environmental changes. Within populations, variation in foraging behaviour and the occurrence of individual tactics in relation to resources distribution can help explain differences in individual fitness, and ultimately identify important factors affecting population dynamics. We examined how foraging behaviour and habitat during the breeding period related to the physiological state of a long‐ranging seabird adapted to sea ice, the Antarctic petrel Thalassoica antarctica. Firstly, using GPS tracking and state‐switching movement modelling (hidden Markov models) on 124 individual birds, we tested for the occurrence of distinct foraging tactics within our study population. Our results highlight a large variation in the movement and foraging behaviour of a very mobile seabird, and delineate distinct foraging tactics along a gradient from foraging in dense pack ice to foraging in open water. Secondly, we investigated the effects of these foraging tactics on individual state at return from a foraging trip. We combined movement data with morphometric and physiological measurements of a suite of plasma metabolites that provided a general picture of a bird's individual state. Foraging in denser sea ice was associated with lower gain in body mass during brooding, as well as lower level of energy acquisition (plasma triacylglycerol) during both brooding and incubation. We found no clear relationship between the foraging tactic in relation to sea ice and the energetic stress (changes in plasma corticosterone), energetic balance (β‐hydroxybutyrate) or trophic level (δ15N). However, a shorter foraging range was related to both the energetic balance (positively) and the trophic level (negatively). Our results highlight a diverse range of foraging tactics in relation to sea ice in Antarctic petrels. While the various foraging tactics do not seem to strongly alter energetic balance, they may affect other aspects of Antarctic petrels' physiology. Future changes in sea‐ice habitats can thus be expected to have an impact on the individual state of seabirds such as Antarctic petrels, which could ultimately affect their population dynamics. Nonetheless, strong individual heterogeneity in the use of sea‐ice habitats by a typical pagophilic species might strengthen its resilience to environmental changes and in particular to forecasted sea‐ice loss. A free Plain Language Summary can be found within the Supporting Information of this article.

Alterations in sperm-inherited noncoding RNAs associate with late-term fetal growth restriction induced by preconception paternal alcohol use

Using a mouse model, our group recently described an association between chronic paternal alcohol use prior to conception and deficits in offspring growth. Here, we sought to determine the impact of alcohol exposure on male reproductive physiology and the association of sperm-inherited noncoding RNAs with the transmission of the observed growth defects. Alcohol exposure did not appreciably alter male reproductive physiology or fertility. However, chronic alcohol use reproducibly induced late-term fetal growth restriction in the offspring, which correlated with a shift in the proportional ratio of transfer RNA-derived small RNAs to Piwi-interacting RNAs, as well as altered enrichment of microRNAs miR21, miR30, and miR142 in alcohol-exposed sperm. Although our dataset share similarities to prior works examining the impact of paternal stress on offspring phenotype, we were unable to identify any changes in plasma corticosterone, indicating alcohol may alter sperm-inherited noncoding RNAs through distinct mechanisms.

Adrenocortical responses in Japanese quail classified by their permanence in proximity to either low or high density of conspecifics.

The density-related permanence test (DRP) is used to classify young birds (while in groups) according to their individual permanence in proximity to either a high or low density of conspecifics (HD or LD, respectively). The birds' performance in DRP was associated with underlying differences in the social responses of their individuals. Quails in homogeneous groups of LD residents responded with less compact groups and higher levels of agonistic interactions to the presence of an intruder, and showed higher levels of agonistic interactions among cagemates than the homogeneous groups of HD birds. This study deepen the characterization of DRP evaluating whether contrasting behavior during test is associated with birds' stress responses to challenging situations during rearing. Plasma corticosterone responses were individually assessed after submitting DRP categorized birds to a brief (10min) partial restraint (mechanical stressor; experiment 1), or after introducing them during 5min as intruders in homogeneous groups of 6 unknown same category (HD or LD) conspecifics (social stressor; experiment 2). Experiment 1 showed that basal corticosterone levels were similar in all groups and the partial mechanical restraint induced an increase in plasma corticosterone concentration also in all groups. However, the increase induced by the stressor was higher in the LD birds than in their HD counterparts. In experiment 2, compared to controls, social stressor showed no plasma corticosterone changes in the intruders that were introduced in an unfamiliar group of HD conspecifics. However, intruders (both HD and LD) that were visiting the LD residents showed an increased corticosterone response compared to their control counterparts. Results suggest that categorization of birds in the DRP test could have relevance for selection programs oriented to obtain birds better suited to intensive rearing conditions that includes high density of animals and exposure to unavoidable stressors.

BLUNTED RESPONSE TO STRESS IN YOUNG IL-10TM/TM MICE: IMPLICATION FOR THE VULNERABILITY IN FRAILTY

AbstractThe hypothalamic pituitary adrenal axis (HPA axis) is a major neuroendocrine system for stress response and for regulating the immune system. Aged rats as well as older humans demonstrate progressive loss of control of the HPA axis, resulting in impaired diurnal rhythm and hypersecretion of glucocorticoids during times of stress. Higher levels and a blunted diurnal rhythm of cortisol have been observed in frail compared to more robust older adults. Understanding the factors underlying disturbed glucocorticoid secretion that precede age-related diseases and frailty are of considerable importance to prevent vulnerability and disability in late life. In order to study this system in vivo, we utilized a mouse model of chronic inflammation and as frailty and measured changes in plasma corticosterone and pro-inflammatory levels after acute cold stress. The plasma corticosterone level was determined 2 weeks before cold stimulation in 10 young (3 months), 10 old (21 months) C57BL/6J mice, and 10 young IL-10 tm/tm (3 months). 5 mice from each group were exposed to cold stress, the remainder served as controls and were not exposed to cold. The treatment groups were exposed to four degrees Celsius for 5 hours and the controls were kept in room temperature conditions at twenty five degrees Celsius. The results showed higher basal plasma corticosterone (P<0.01) and normal IL-6 and TNFR-1 levels in young IL-10tm/tm, compared to young and old C57BL/6J mice. However, there were unchanged corticosterone level and higher IL-6 and TNFR-1 levels (P=0.04, 0.02, respectively) in young IL-10tm/tm mice after acute cold stress compared to young wild type mice. Lower GRa mRNA expression in hippocampus was also observed in control and treated young IL-10tm/tm (P<0.01), compared the age-matched wild type mice. These findings provide initial evidence for the hypothesis that HPA axis dysfunction is through whole life of frail subjects and even earlier than changes in immune system.

Effects of the combination of metyrapone and oxazepam on cocaine-induced increases in corticosterone in the medial prefrontal cortex and nucleus accumbens

We have previously demonstrated that a combination of drugs (i.e., metyrapone and oxazepam) known to attenuate HPA-axis activity effectively decreases cocaine self-administration and cue reactivity in rats. However, we did not find changes in plasma corticosterone that matched the behavioral effects we observed, indicating that a different mechanism of action must be involved. Therefore, we hypothesized that the combination of metyrapone and oxazepam attenuates cocaine taking and seeking by decreasing cocaine-induced increases in corticosterone in the brain. Male rats were implanted with guide cannulae targeting the medial prefrontal cortex or nucleus accumbens. After the rats recovered from surgery, the microdialysis session was conducted. Rats were housed in the experimental chamber and the dialysis probes inserted into the guide cannulae the night before the session. The following day, dialysate samples were collected over a five-hour session. Baseline samples were collected for the first two hours, every 20min. Samples were then collected following administration of cocaine (15mg/kg, ip). Before injections of cocaine, rats were pretreated with either vehicle or the combination of metyrapone (50mg/kg, ip) and oxazepam (10mg/kg, ip). The administration of cocaine resulted in an increase in corticosterone in the medial prefrontal cortex following vehicle pretreatment, which was not observed in the nucleus accumbens. This cocaine-induced increase in corticosterone was attenuated by metyrapone/oxazepam. Reducing cocaine-induced increases in corticosterone in the medial prefrontal cortex might represent a novel mechanism through which the combination of metyrapone/oxazepam produces its behavioral effects.

Long-term effects of pre-pubertal fluoxetine on behaviour and monoaminergic stress response in stress-sensitive rats.

Although prescription rates of antidepressants for children and adolescents have increased, concerns have been raised regarding effects on neurodevelopment and long-term outcome. Using a genetic animal model of depression, this study investigated the long-term effects of pre-pubertal administration of fluoxetine (FLX) on depressive-like behaviour in early adulthood, as well as on central monoaminergic response to an acute stressor. We postulated that pre-pubertal FLX will have lasting effects on animal behaviour and monoaminergic stress responses in early adulthood. Flinders sensitive line (FSL) rats received 10 mg/kg/day FLX subcutaneously from postnatal day 21 (PnD21) to PnD34 (pre-pubertal). Thereafter, following normal housing, rats were either subjected to locomotor testing and the forced swim test (FST) on PnD60 (early adulthood), or underwent surgery for microdialysis, followed on PnD60 by exposure to acute swim stress and measurement of stressor-induced changes in plasma corticosterone and pre-frontal cortical monoamine concentrations. Pre-pubertal FLX did not induce a late emergent effect on immobility in FSL rats on PnD60, whereas locomotor activity was significantly decreased. Acute swim stress on PnD60 significantly increased plasma corticosterone levels, and increased pre-frontal cortical norepinephrine (NE) and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations. Pre-pubertal FLX significantly blunted the pre-frontal cortical NE and 5-HIAA response following swim stress on PnD60. Baseline dopamine levels were significantly enhanced by pre-pubertal FLX, but no further changes were induced by swim stress. Pre-pubertal FLX did not have lasting antidepressant-like behavioural effects in genetically susceptible, stress-sensitive FSL rats. However, such treatment reduced locomotor activity, abrogated noradrenergic and serotonergic stressor responses and elevated dopaminergic baseline levels in adulthood.

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress

Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal.

Innate immunity and testosterone rapidly respond to acute stress, but is corticosterone at the helm?

When faced with a stressor, vertebrates can rapidly increase the secretion of glucocorticoids, which is thought to improve the chances of survival. Concurrent changes in other physiological systems, such as the reproductive endocrine or innate immune systems, have received less attention, particularly in wild vertebrates. It is often thought that glucocorticoids directly modulate immune performance during a stress response, but, in many species, androgens also rapidly respond to stress. However, to our knowledge, no study has simultaneously examined the interactions between the glucocorticoid, androgen, and innate immune responses to stress in a wild vertebrate. To address this issue, we tested the hypothesis that the change in plasma corticosterone (CORT) in response to the acute stress of capture and restraint is correlated with the concurrent changes in plasma testosterone (T) and innate immune performance (estimated by the capacity of plasma to agglutinate and lyse foreign cells) in the Abert's Towhee (Melozone aberti). Furthermore, to broaden the generality of the findings, we compared male and female towhees, as well as males from urban and non-urban populations. Acute stress increased plasma CORT, decreased plasma T in males, and decreased innate immune performance, but the increase in CORT during stress was not correlated with the corresponding decreases in either plasma T or innate immunity. By contrast, the plasma T stress response was positively correlated with the innate immune stress response. Collectively, our results challenge the proposition that the glucocorticoid stress response is correlated with the concurrent changes in plasma T, a key reproductive hormone, and innate immunity, as estimated by agglutination and lysis.

Effect of Temporary Inactivation of Nucleus Accumbens on Chronic Stress Induced by Electric Shock to the Sole of the Foot in Female NMRI Mice

BACKGROUND AND OBJECTIVE: Activity changes in the neurons of nucleus accumbens during stress have been previously identified. However, the role of nucleus accumbens in diminishing stress-induced side-effects is not fully understood. In this study, we aimed to evaluate the effects of temporary inactivation of nucleus accumbens on stressinduced metabolic changes in female mice. METHODS: This experimental study was performed on 48 female NMRI mice with an average 27±3 g. The nucleus accumbens was unilaterally and bilaterally cannulated. After one week of recovery, 2% lidocaine or saline was administered in mice for four consecutive days (5 min per day) before inducing electric shock to the sole of the foot. Plasma corticosterone level, food and water intake, and delay in eating were assessed as stress-induced metabolic parameters. FINDINGS: Stress lonely, caused an increase in plasma corticosterone (17±0.8) compared with the control group (4.5±0.3) (p<0.001). It also, caused an increase delay in eating (%218±9.8, p<0.01) and, decrease water (%80±4.5) and food (%84±5.5) intake (p<0.05). Temporary inactivation of nucleus accumbens did not affect the stress-induced changes in plasma corticosterone, and it suppressed the effect of stress on the amount of water intake; inactivation of the left nucleus accumbens was more effective (%195±7.6, p<0.01). Temporary inactivation of nucleus accumbens neutralized the effect of stress on the amount of food intake. Temporary inactivation of the right nucleus accumbens augmented the effect of stress on delay in eating (%264±10.8, p<0.01), and inactivation of the left nucleus accumbens could suppress this effect. CONCLUSION: It seems that temporary inactivation of nucleus accumbens can be effective in diminishing stressinduced metabolic changes. However, this influence is indicative of asymmetry in the function of right and left nucleus

Blood-feeding ectoparasites as developmental stressors: Does corticosterone mediate effects of mite infestation on nestling growth, immunity and energy availability?

How resources are distributed to growth and self-maintenance early in life is likely to impact survival and reproduction. Early resource allocation decisions may be particularly critical in altricial birds, as they have rapid developmental trajectories, and may be highly susceptible to environmental factors that can perturb development. The aim of this study was to determine if blood-feeding ectoparasites act as developmental stressors in European starling (Sturnus vulgaris) nestlings, driving a trade-off between growth and immunity. We hypothesized that because ectoparasites compete for resources they would induce growth-immunity trade-offs in parasitized nestlings. We also tested the hypothesis that changes in plasma corticosterone mediate the effects of ectoparasites on growth and immunity. Throughout development we assessed between-nest variation in ectoparasite density, measured growth, and a variety of blood parameters, including plasma corticosterone. We also assessed immune function across development. We found that nestlings from nests with high levels of ectoparasites were smaller, had elevated blood glucose, lower hematocrit levels, and appeared to engage in compensatory growth prior to fledging. They also had elevated innate immune responses early, but reduced responses later relative to nestlings from nests with low levels of ectoparasites. Plasma corticosterone was not affected by ectoparasite load, but did increase with nestling age. Overall, we find evidence that ectoparasites are developmental stressors that affect growth-immunity trade-offs, but their effects do not appear to be mediated by changes in circulating levels of corticosterone.

A rodent model of traumatic stress induces lasting sleep and quantitative electroencephalographic disturbances.

Hyperarousal and sleep disturbances are common, debilitating symptoms of post-traumatic stress disorder (PTSD). PTSD patients also exhibit abnormalities in quantitative electroencephalography (qEEG) power spectra during wake as well as rapid eye movement (REM) and non-REM (NREM) sleep. Selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological treatment for PTSD, provide modest remediation of the hyperarousal symptoms in PTSD patients, but have little to no effect on the sleep-wake architecture deficits. Development of novel therapeutics for these sleep-wake architecture deficits is limited by a lack of relevant animal models. Thus, the present study investigated whether single prolonged stress (SPS), a rodent model of traumatic stress, induces PTSD-like sleep-wake and qEEG spectral power abnormalities that correlate with changes in central serotonin (5-HT) and neuropeptide Y (NPY) signaling in rats. Rats were implanted with telemetric recording devices to continuously measure EEG before and after SPS treatment. A second cohort of rats was used to measure SPS-induced changes in plasma corticosterone, 5-HT utilization, and NPY expression in brain regions that comprise the neural fear circuitry. SPS caused sustained dysregulation of NREM and REM sleep, accompanied by state-dependent alterations in qEEG power spectra indicative of cortical hyperarousal. These changes corresponded with acute induction of the corticosterone receptor co-chaperone FK506-binding protein 51 and delayed reductions in 5-HT utilization and NPY expression in the amygdala. SPS represents a preclinical model of PTSD-related sleep-wake and qEEG disturbances with underlying alterations in neurotransmitter systems known to modulate both sleep-wake architecture and the neural fear circuitry.

Acute stress in adulthood impoverishes social choices and triggers aggressiveness in preclinical models.

Adult C57BL/6J mice are known to exhibit high level of social flexibility while mice lacking the β2 subunit of nicotinic receptors (β2−/− mice) present social rigidity. We asked ourselves what would be the consequences of a restraint acute stress (45 min) on social interactions in adult mice of both genotypes, hence the contribution of neuronal nicotinic receptors in this process. We therefore dissected social interaction complexity of stressed and not stressed dyads of mice in a social interaction task. We also measured plasma corticosterone levels in our experimental conditions. We showed that a single stress exposure occurring in adulthood reduced and disorganized social interaction complexity in both C57BL/6J and β2−/− mice. These stress-induced maladaptive social interactions involved alteration of distinct social categories and strategies in both genotypes, suggesting a dissociable impact of stress depending on the functioning of the cholinergic nicotinic system. In both genotypes, social behaviors under stress were coupled to aggressive reactions with no plasma corticosterone changes. Thus, aggressiveness appeared a general response independent of nicotinic function. We demonstrate here that a single stress exposure occurring in adulthood is sufficient to impoverish social interactions: stress impaired social flexibility in C57BL/6J mice whereas it reinforced β2−/− mice behavioral rigidity.

The Ventral Ascending Noradrenergic Bundles Are Involved in the Stress Response to Immobilization in Rats

Stressful stimuli induced by immobilization are perceived as acute stress in rats. This acute stress activates corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), resulting in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. The ventral ascending noradrenergic bundles (V-NAB) from the brainstem innervate the PVN. To investigate the relationship between the response of the HPA axis and the V-NAB, we examined changes in plasma corticosterone, the final output of the HPA axis, and extracellular noradrenaline (NA) in the PVN following immobilization stress in rats that received bilateral 6-hydroxydopamine (6-OHDA) lesions of the V-NAB. 6-OHDA microinjection into the V-NAB reduced the magnitude of the responses of plasma corticosterone and extracellular NA in the PVN following immobilization stress. Our results suggest that V-NAB innervation of the PVN is involved in immobilization stress-induced activation of the HPA axis.

Effect of acute swim stress on plasma corticosterone and brain monoamine levels in bidirectionally selected DxH recombinant inbred mouse strains differing in fear recall and extinction

Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites 3,4-dihydroxyphenyacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 min after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or post-traumatic stress disorder.

Effects of electroconvulsive seizures on depression-related behavior, memory and neurochemical changes in Wistar and Wistar-Kyoto rats.

Investigations in healthy outbred rat strains have shown a potential role for brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis in the antidepressant and memory side effects of electroconvulsive therapy (ECT, or ECS in animals). The Wistar-Kyoto (WKY) rat strain is used as a genetic model of depression yet no studies to date have directly compared the impact of ECS on the WKY strain to its healthy outbred control (Wistar). The objective of this study is to examine behavioral (antidepressant and retrograde memory) and neurochemical (BDNF and HPA axis) changes immediately (1day) and at a longer delay (7days) after repeated ECS (5 daily administrations) in WKY and Wistar rats. Male Wistar and WKY rats received 5days of repeated ECS or sham treatment and were assessed 1 and 7days later for 1) depression-like behavior and mobility; 2) retrograde memory; and 3) brain BDNF protein, brain corticotropin-releasing factor (CRF) and plasma corticosterone levels. Both strains showed the expected antidepressant response and retrograde memory impairments at 1day following ECS, which were sustained at 7days. In addition, at 1day after ECS, Wistar and WKY rats showed similar elevations in brain BDNF and extra-hypothalamic CRF and no change in plasma corticosterone. At 7days after ECS, Wistar rats showed sustained elevations of brain BDNF and CRF, whereas WKY rats showed a normalization of brain BDNF, despite sustained elevations of brain CRF. The model of 5 daily ECS was effective at eliciting behavioral and neurochemical changes in both strains. A temporal association was observed between brain CRF levels, but not BDNF, and measures of antidepressant effectiveness of ECS and retrograde memory impairments suggesting that extra-hypothalamic CRF may be a potential important contributor to these behavioral effects after repeated ECS/ECT.

Transgenerational effects of social stress on social behavior, corticosterone, oxytocin, and prolactin in rats

Social stressors such as depressed maternal care and family conflict are robust challenges which can have long-term physiological and behavioral effects on offspring and future generations. The current study investigates the transgenerational effects of an ethologically relevant chronic social stress on the behavior and endocrinology of juvenile and adult rats. Exposure to chronic social stress during lactation impairs maternal care in F0 lactating dams and the maternal care of the F1 offspring of those stressed F0 dams. The overall hypothesis was that the male and female F2 offspring of stressed F1 dams would display decreased social behavior as both juveniles and adults and that these behavioral effects would be accompanied by changes in plasma corticosterone, prolactin, and oxytocin. Both the female and male F2 offspring of dams exposed to chronic social stress displayed decreased social behavior as juveniles and adults, and these behavioral effects were accompanied by decreases in basal concentrations of corticosterone in both sexes, as well as elevated juvenile oxytocin and decreased adult prolactin in the female offspring. The data support the conclusion that social stress has transgenerational effects on the social behavior of the female and male offspring which are mediated by changes in the hypothalamic–pituitary–adrenal axis and hypothalamic–pituitary–gonadal axis. Social stress models are valuable resources in the study of the transgenerational effects of stress on the behavioral endocrinology of disorders such as depression, anxiety, autism, and other disorders involving disrupted social behavior.

Orexinergic innervation of urocortin1 and cocaine and amphetamine regulated transcript neurons in the midbrain centrally projecting Edinger–Westphal nucleus

Orexin is a neuropeptide that has been implicated in several processes, such as induction of appetite, arousal and alertness and sleep/wake regulation. Multiple lines of evidence also suggest that orexin is involved in the stress response. When orexin is administered intracerebroventricular it activates the hypothalamic pituitary adrenal (HPA)-axis, which is the main regulator of the stress response. The HPA-axis is not the only player in the stress response evidence suggests that urocortin 1 (Ucn1), a member of the corticotropin releasing factor (CRF) neuropeptide family, also plays an important role in the stress response adaptation. Ucn1 is primarily synthetized in the centrally projecting Edinger–Westphal nucleus (EWcp), which also receives dense innervation by orexin terminals. In this study we tested the hypothesis that orexin would directly shape the response of EWcp-Ucn1 neurons to acute cold stress. To test this hypothesis, we first assessed whether orexinergic axon terminals would innervate EWcp-Ucn1/CART neurons, and next we exposed orexin deficient (orexin-KO) male mice and their male wild-type (WT) littermates to acute cold stress for 2h. We also assessed stress-associated changes in plasma corticosterone (CORT), as well as the activation of Ucn1/CART neurons in the EWcp nucleus. We found that orexin immunoreactive axon terminals were juxtaposed to EWcp-Ucn1/CART neurons, which also expressed orexin receptor 1 mRNA. Furthermore, acute stress strongly activated the EWcp-Ucn1/CART neurons and increased plasma CORT in both WT littermates and orexin-KO mice, however no genotype effect was found on these indices. Taken together our data show that orexin in general is not involved in the animal's acute stress response (plasma CORT) and it does not play a direct role in shaping the response of EWcp-Ucn1 neurons to acute stress either.