Acute exposure to a novel stressor further reduces the habituated corticosterone response to restraint in rats

The present study sought to identify dishabituation of the hypothalamic-pituitary-adrenal(HPA) axis response to different psychological stressors. Young adult male Sprague Dawley rats were exposed to five, 1 h sessions of restraint stress on five consecutive days. On the sixth day, and 2 h before additional exposure to restraint, animals were subjected to 30 min of a small (27cm square), elevated open field stressor (pedestal), which served as the dishabituating stimulus. We predicted HPA axis response dishabituation in chronically restrained rats exposed to the novel pedestal. Rats which underwent five days of restraint stress showed significantly blunted plasma corticosterone levels to restraint (habituation) as compared to restraint-nai've rats. However, rats which underwent five sessions of restraint responded with an enhanced habituation response when confronted with restraint shortly after exposure to the novel pedestal. Instead of HPA axis response dishabituation, we observed enhanced habituation. Subsequent experiments determined that a 1.25 mgkg corticosterone injection could substitute for pedestal exposure to produce enhanced restraint habituation.Combined treatment with both the glucocorticoid receptor antagonist RU40555 (30 mgkg)and the mineralocorticoid receptor antagonist RU283 18 (50 mgkg) blocked the expression of enhanced habituation after pedestal exposure. Thus, the delayed corticosterone negative feedback produced by novel stress led to enhanced expression of corticosterone response habituation.     

Adaptation of anterior pituitary hormones to chronic noise stress in male rats

We have studied the effects of acute and chronic noise on serum levels of pituitary hormones in male Wistar rats. Acute noise increased serum levels of corticosterone, prolactin, and luteinizing hormone and decreased serum GH. FSH was unaffected by this stressor. Chronic noise did not modify basal levels of any hormone studied, however responsiveness of some hormones to the same stimuli was altered. Reduced corticosterone, prolactin, and GH responses to noise was observed after previous chronic exposure to this stimuli. LH response followed the same pattern although it did not reach statistical significance. It might be concluded that adaptation to a repeated stress stimulus is not confined to the pituitary-adrenal axis, however, the degree of adaptation could vary between different hormones.     

Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder

People who are exposed to horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). Some of the symptoms of PTSD include persistent anxiety, exaggerated startle, cognitive impairments and increased sensitivity to yohimbine, an alpha(2)-adrenergic receptor antagonist. We have taken into account the conditions known to induce PTSD, as well as factors responsible for long-term maintenance of the disorder, to develop an animal model of PTSD. Adult male Sprague-Dawley rats were administered a total of 31 days of psychosocial stress, composed of acute and chronic components. The acute component was a 1-h stress session (immobilization during cat exposure), which occurred on Days 1 and 11. The chronic component was that on all 31 days the rats were given unstable housing conditions. We found that psychosocially stressed rats had reduced growth rate, reduced thymus weight, increased adrenal gland weight, increased anxiety, an exaggerated startle response, cognitive impairments, greater cardiovascular and corticosterone reactivity to an acute stressor and heightened responsivity to yohimbine. This work demonstrates the effectiveness of acute inescapable episodes of predator exposure administered in conjunction with daily social instability as an animal model of PTSD.     

Acute stress rapidly and persistently enhances memory formation in the male rat

Previous studies, as well as the present one, report that acute exposure to intermittent tailshocks enhances classical eyeblink conditioning in male rats when trained 24 h after stressor cessation. In Experiment 1, it was determined that the facilitating effect of stress on conditioning could also be obtained in response to a stressor of acute inescapable swim stress but not inescapable noise or the unconditioned stimulus of periorbital eyelid stimulation. These selective responses arose despite comparable enhancements of the stress-related hormone corticosterone in response to tailshocks, periorbital eyelid stimulation, noise stress, and supraelevation in response to swim stress. Although corticosterone is necessary for the enhanced learning in response to stress (Beylin & Shors, 1999), these results suggest that it is not sufficient. In addition, the results suggest that the enhancement is not dependent on common characteristics between the stressor and the conditioning stimuli (stimulus generalization). In Experiment 2, it was determined that the facilitating effect of the stressor on conditioning occurs within 30 min of stressor cessation. Thus, the mechanism responsible for facilitating memory formation is rapidly induced as well as persistently expressed. In Experiment 3, it was determined that exposure to the stressor does not enhance performance of the conditioned response after the response has been acquired. Thus, exposure to the stressor enhances the formation of new associations rather than affecting retention or performance of the motor response. These studies extend the circumstances under which stress is known to enhance associative learning and implicate neural mechanisms of memory enhancement that are rapidly induced and persistently expressed.     

Persistent neuroendocrine changes in multiple hormonal axes after a single or repeated stressor exposures

Many researchers have studied acute responses to stress in animals and how they are modified by prior stressor exposure, but relatively few have examined whether responses to stressors might last for prolonged periods of time. We have previously demonstrated that trough plasma corticosterone levels in rats are elevated for three to five days after single or repeated exposures to mild restraint and inescapable tailshock. The current study measured other aspects of the adrenal axis, and activity in other neuroendocrine systems, 24 hours after one or three consecutive exposures to the same stress paradigm. The data indicated persistent activation of the adrenal axis and prolactin levels, whereas the thyroid and reproductive hormone axes were inhibited after either one or three stress sessions. These changes are remarkable in that one would have expected acute responses to even intense stressors to have ended within hours after the end of the stressor. It will be important to understand the interactions among these responding neuroendocrine systems and to know how long such persistent changes last. Finally, it will be critical to understand the relative contributions of neuroendocrine and psychological factors in maintaining these persistent neuroendocrine changes after exposure to intense stressors.     

Aggravation of DSS-induced colitis after chronic subordinate colony (CSC) housing is partially mediated by adrenal mechanisms

Chronic subordinate colony housing (CSC) is a relevant chronic psycho-social stressor for male mice. Here, we investigated effects of CSC on the severity of dextran sulphate sodium (DSS)-induced colitis and the involvement of adrenal mechanisms. After 19 days of CSC, male C57BL/6 mice were treated with 1% DSS (8 days). After 8 days, inflammatory shortening of the colon and the histological inflammation score were increased in CSC mice. Additionally, the increased secretion of pro-inflammatory cytokines by mesenteric lymph node cells found on day 2 and 4 of DSS treatment was down-regulated in CSC mice on day 8 of DSS treatment, paralleled by an increase in plasma corticosterone. In contrast, in unstressed controls, elevation of cytokine secretion was delayed and only found on day 8 of DSS treatment, associated with a prompt rise in plasma corticosterone. To reveal adrenal mechanisms in CSC-induced effects on colitis, mice were adrenalectomized, exposed to CSC and treated with DSS (8 days). In adrenalectomized CSC mice, the severity of DSS-induced colitis was reduced, as body weight loss, shortening of colon, histological damage score, and cytokine secretion from mesenteric lymph node cells were diminished compared with sham-operated CSC mice. In conclusion, exposure to chronic psycho-social stress increases the severity of acute DSS colitis, an effect which is, at least partly, mediated by adrenal mechanisms.     

c-fos mRNA induction in acute and chronic audiogenic stress: possible role of the orbitofrontal cortex in habituation

To study putative brain circuits involved in habituation to stress, rats were exposed daily (30 min for 15 days) to an environment in the presence (Chronic) or absence (Acute) of loud noise (105 dB sound pressure level--SPL A Scale). Behavioral and endocrine measures of stress were taken throughout this habituation period, and both measures displayed strong habituation in the Chronic group. All rats were killed immediately after the day 16 exposure, constituting an acute stressor for the Acute group, and regional brain activity was assessed using c-fos mRNA induction with in situ hybridization. Hearing damage could not easily explain these results because additional rats exposed to a similar stress protocol exhibited no changes in auditory brainstem evoked potentials. c-fos mRNA induction in the central auditory system was similar between the Acute and Chronic groups, particularly at lower auditory processing levels, also arguing against a simple reduction in auditory processing in the chronically stressed rats. However, c-fos mRNA expression was reduced in chronically, as compared to acutely, stressed rats in several regions previously implicated in audiogenic stress (lateral septum, bed nucleus of the stria terminalis, some preoptic areas, and the paraventricular hypothalamic nucleus). Interestingly, the orbitofrontal cortex was the only region displaying higher c-fos mRNA induction in the chronically as compared to acutely stressed rats. This region has connections to several stress-responsive areas and may thus be a critical region actively inhibiting stress.     

Differing effects of acute and chronic stressors on plasma osteocalcin and leptin in rats

Stressor activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis can have profound effects on bone and also appetite and metabolism. We tested in rats the response of plasma osteocalcin (pOC, a bone biomarker that is acutely stress responsive), corticosterone, and leptin to (1) ethanol consumption (5% w/v) in a liquid diet (compared with ad libitum and pair-fed rats), (2) acute restraint, and (3) acute (once, 1 h) and (4) chronic (1 h/day for 7 weeks) social aggression. Basal pOC concentration did not differ with ethanol diet or social interaction, but was elevated by both foot restraint immobilization (Imo) and restraint in wire mesh cylinders (WMR). As previously reported for chronic Imo, ingestion of ethanol blunted the pOC response to Imo. Plasma corticosterone concentration was increased by acute WMR and acute social interaction but was unaltered by chronic social interaction. Plasma leptin concentration was markedly increased by Imo in ad libitum fed, but only slightly in ethanol or pair-fed rats. In contrast, the data reflect significant differences between acute and chronic stressor effects since chronic social stress had little effect on pOC or plasma corticosterone, but tended to decrease leptin level in relation to dominance. Lack of significant impact of prolonged ethanol intake or social aggression suggests physiological adaptation.     

Effects of voluntary wheel running on heart rate, body temperature, and locomotor activity in response to acute and repeated stressor exposures in rats

Stress often negatively impacts physical and mental health but it has been suggested that voluntary physical activity may benefit health by reducing some of the effects of stress. The present experiments tested whether voluntary exercise can reduce heart rate, core body temperature and locomotor activity responses to acute (novelty or loud noise) or repeated stress (loud noise). After 6 weeks of running-wheel access, rats exposed to a novel environment had reduced heart rate, core body temperature, and locomotor activity responses compared to rats housed under sedentary conditions. In contrast, none of these measures were different between exercised and sedentary rats following acute 30-min noise exposures, at either 85 or 98 dB. Following 10 weeks of running-wheel access, both groups displayed significant habituation of all these responses to 10 consecutive daily 30-min presentations of 98 dB noise stress. However, the extent of habituation of all three responses was significantly enhanced in exercised compared to sedentary animals on the last exposure to noise. These results suggest that in physically active animals, under some conditions, acute responses to stress exposure may be reduced, and response habituation to repeated stress may be enhanced, which ultimately may reduce the negative and cumulative impact of stress.     

Chronic corticosterone-induced deterioration in rat behaviour is not paralleled by changes in hippocampal NF-kappaB-activation

We investigated whether long-lasting stress induced by chronic glucocorticoid (GC) exposure affects activation of brain NF-kappaB and whether these changes are related to functional deterioration and structural changes in the rat hippocampus. Psychometric investigations were conducted using a holeboard test system in 28 one-year-old male Wistar rats. Thereafter, rats were divided into three groups for daily administration of 10 mg corticosterone (treatment) or sesame oil (placebo = sham control for effects of the vehicle) for 60 days. Additional control rats did not receive any treatment or handling until the end of the experiment. Behavioural and cognitive changes were tested again in the holeboard system. Rat body weights and corticosterone concentrations in plasma, hippocampus and urine were determined and adrenal glands were investigated histopathologically. Hippocampal concentrations of corticosterone, NF-kappaB and I-kappaBalpha were determined using RIA, EMSA and Western blotting techniques, respectively. Structural changes in rat hippocampus were measured using magnetic resonance imaging techniques. High peripheral corticosterone concentrations after chronic treatment led to significant reductions in rat body weight. Significant atrophy of both adrenal glands with marked histological deterioration was detected. Furthermore, an increase in hippocampal corticosterone concentrations was observed after chronic administration. Chronic corticosterone treatment also significantly altered behaviour and working and reference memory capacity without changing hippocampal structure. Daily injections of sesame oil in the placebo group, however, were also sufficient to reduce the pellet-finding time. However, neither in the corticosterone group nor in the placebo group were behavioural changes paralleled by significant changes in brain NF-kappaB activation and I-kappaBalpha expression. Thus, cognitive alterations in rats seen after chronic corticosterone exposure are not paralleled by hippocampal NF-kappaB modulation.     

The adaptive response of adult rat Leydig cells to repeated immobilization stress: the role of protein kinase A and steroidogenic acute regulatory protein

The ability of immobilization stress (IMO) to decrease Leydig cell steroidogenesis and serum androgen concentration has been previously observed, but the possible mechanism(s) involved in the adaptation to prolonged or repeated stress have not been identified. In this study, we investigated whether the Leydig cells obtained from adult rats subjected to acute (15 min, 30 min or 2 h) and repeated (2 or 10 days, 2 h daily) IMO show adaptive mechanism(s) in response to stress-impaired steroidogenesis. The results showed that basal and human chorionic gonadotropin-stimulated cAMP production by Leydig cells isolated from rats exposed to both acute and repeated IMO was significantly reduced. Despite the reduced cAMP production, immunoblot analysis revealed increased immunoreactivity for both protein kinase A (PKA) and steroidogenic acute regulatory (StAR) protein in Leydig cells obtained from rats repeatedly exposed to IMO. Also, the phosphorylation and production of mature StAR protein was evident during exposure of rats to repeated IMO treatment. Treatment with cholesterol, the steroid substrate transported into mitochondria by StAR, significantly increased androgen and progesterone production by Leydig cells isolated from rats exposed to repeated IMO. In contrast, when other steroid substrates (22(R)-OH-cholesterol, pregnenolone, progesterone, Delta4-androstenedione) were present in the culture media, Leydig cell steroidogenesis was still reduced by IMO. Thus, PKA-mediated phosphorylation of StAR protein is an important mechanism in the adaptive response of Leydig cells to repeated IMO.     

Nimodipine Counteracts Corticosterone-Induced Habituation Impairments

Corticosterone or placebo sustained-release pellets (4 pellets of 200 mg each, released over 90 days) were implanted subcutaneously in young Fischer-344 rats, fed with either regular food or with food containing 860 ppm of nimodipine. Following 2 weeks of treatment, the habituation of the rats to a new environment was studied. On the first test day, placebo-implanted rats explored the new environment and exhibited a characteristic habituation. On the second test day, 48 hr later, low activity was measured in the already familiar environment. This habituation was absent in corticosterone-implanted rats fed with regular food. However, corticosterone-implanted rats fed with food containing nimodipine behaved during the second test similarly to the placebo-implanted group. The data indicated that the behavioral deficit, induced in Fischer-344 rats by the high corticosterone levels, was reversed by the nimodipine treatment. Thus, nimodipine may be useful in counteracting certain prolonged stress-related cognitive impairments.     

Serial stressors: prior exposure to a stressor modulates its later effectiveness on gastric ulceration and corticosterone release

Several studies have focused on the proactive effects of prior exposure to a stressor on ulcerogenic and endocrine responses to exposure to a similar final stressor. In the present study, we explored the effects of prior exposure of M?ll-Wistar rats to water-restraint stress on gastric ulceration and corticosterone responses to a final stressor. The number of prior exposures to water-restraint challenge was varied from one to four, and the durations of the prior exposures varied from 30 min to 2 h. The duration of the final stress challenge was 75 min. The two indices of the stress response to the final stressor challenge yielded different results. For neither index was the duration of prior exposures a significant factor in modulating the response to the final challenge. For gastric ulceration, those animals receiving one prior exposure, but not four, exhibited less gastric ulceration than animals receiving no prior exposure. These animals also developed less ulceration than those receiving four prior exposures. For corticosterone, those animals receiving four prior exposures exhibited a lower adrenocortical response to the final stressor than did animals receiving no prior exposure, or only one prior exposure. The results indicate the complexity of proactive effects of earlier stress experience on responses to a final stressor challenge.     

Neuronal nitric oxide synthase gene inactivation reduces the expression of vasopressin in the hypothalamic paraventricular nucleus and of catecholamine biosynthetic enzymes in the adrenal gland of the mouse

The impact of a lifelong absence of the neuronal nitric oxide synthase (nNOS) in the neuroendocrine stress response was investigated in nNOS knockout (KO) and wild type (WT) mice under basal conditions and in response to forced swimming. In the hypothalamic paraventricular nucleus oxytocin and corticotropin-releasing-hormone mRNA levels did not differ between these genotypes under resting conditions, whereas vasopressin mRNA levels were significantly lower in nNOS KO than in WT animals. Also, in the adrenal glands basal levels of tyrosine hydroxylase protein, the rate-limiting enzyme for catecholamine biosynthesis, and of phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine, were significantly reduced in nNOS KO mice. Plasma adrenocorticotropin, corticosterone, norepinephrine and epinephrine levels were similar in the KO and WT genotypes under resting conditions. In response to forced swimming, a similar increase in plasma adrenocorticotropin and corticosterone was observed in KO and WT animals. Stressor exposure triggered also an increased epinephrine release in WT animals, but did not significantly alter plasma epinephrine levels in KO mice. These data suggest that the chronic absence of nNOS reduces the capacity of epinephrine synthesising enzymes in the adrenal gland to respond to acute stressor exposure with an adequate epinephrine release.     

Intermittent exposure to social defeat and open-field test in rats: acute and long-term effects on ECG,body temperature and physical activity

This study investigated the effects of exposure to an intermittent homotypic stressor on: (i) habituation of acute autonomic responsivity (i.e. cardiac sympathovagal balance and susceptibility to arrhythmias), and (ii) circadian rhythmicity of heart rate, body temperature, and physical activity. After implantation of a transmitter for the radiotelemetric recording of electrocardiogram (ECG), body temperature and physical activity, adult male rats (Rattus norvegicus, Wild Type Groningen strain) were repeatedly exposed (10 consecutive times, on alternate days) to either a social stressor (defeat by a con-specific, n = 15) or an open-field, control challenge (transfer to a new cage; n = 8). ECGs, body temperature and physical activity were continuously recorded in baseline, test and recovery periods (each lasting 15 min), at the 1st and 10th episodes of both defeat and open-field challenge. The circadian rhythms of heart rate, body temperature and physical activity were monitored before (5 days), during (16 days) and after (21 days) the intermittent stress protocol. This study indicates that there is no clear habituation of either acute cardiac autonomic responsivity (as estimated by means of time-domain indexes of heart rate variability) or arrhythmia occurrence to a brief, intermittent, homotypic challenge, regardless of the nature of the stressor (social or non-social). On the other hand, rats exposed to social challenge also failed to show adaptation of acute temperature and activity stress responsiveness, whereas rats facing open-field challenge developed habituation of activity and sensitization of temperature responses. Repeated social challenge produced remarkable reductions of the heart rate circadian rhythm amplitude (this effect being significantly greater than that produced by intermittent open-field), but only minor changes in the daily rhythms of body temperature and physical activity.     

Active coping with stress suppresses glucose metabolism in the rat hypothalamus

We used 18F-fluorodeoxyglucose small-animal positron-emission tomography to determine whether different styles of coping with stress are associated with different patterns of neuronal activity in the hypothalamus. Adult rats were subjected to immobilization (IMO)-stress or to a non-immobilized condition for 30 min, in random order on separate days, each of which was followed by brain-scanning. Some rats in the immobilized condition were allowed to actively cope with the stress by chewing a wooden stick during IMO, while the other immobilized rats were given nothing to chew on. Voxel-based statistical analysis of the brain imaging data shows that chewing counteracted the stress-induced increased glucose uptake in the hypothalamus to the level of the non-immobilized condition. Region-of-interest analysis of the glucose uptake values further showed that chewing significantly suppressed stress-induced increased glucose uptake in the paraventricular hypothalamic nucleus and the anterior hypothalamic area but not in the lateral hypothalamus. Together with the finding that the mean plasma corticosterone concentration at the termination of the IMO was also significantly suppressed when rats had an opportunity to chew a wooden stick, our results showed that active coping by chewing inhibited the activation of the hypothalamic-pituitary-adrenal axis to reduce the endocrine stress response.     

Hypothalamo-Pituitary-Adrenocortical Regulation Following Lesions of the Central Nucleus of the Amygdala

Previous reports indicate that the central nucleus of the amygdala (CeA) stimulates adrenocorticotropin and corticosterone secretion, suggesting a role for this region in central hypothalamo-pituitary-adrenocortical (HPA) stress regulation. To evaluate this hypothesis, this study assessed the impact of CeA lesion on the response of hypophysiotrophic paraventricular nucleus (PVN) neurons to acute restraint and chronic unpredictable stress exposure. In contrast to previous reports, CeA lesions did not affect corticosterone or ACTH secretion induced by acute stress. Acute restraint increased PVN corticotropin releasing hormone (CRH) mRNA expression, increased the number of parvocellular PVN neurons expressing the co-secretagogue arginine vasopressin (AVP), and induced cFOS mRNA expression in the parvocellular PVN. However, there was no additional effect of CeA lesion on any measure of PVN activation. Chronic unpredictable stress exposure induced long-term activation of the HPA axis, noted by thymic involution, adrenal hypertrophy and increased PVN CRH mRNA expression. Stress-induced changes in thymus and adrenal weights were not affected by CeA lesion. Further, CeA lesion rats did not differ from controls in post-stress CRH mRNA expression. However, basal CRH mRNA expression was increased in the PVN of CeA rats, suggesting that the CeA plays a role in long-term inhibition of the PVN. The results of these studies are not consistent with the hypothesis that the CeA is necessary for stress-induced pituitary-adrenocortical activation. Rather, this region may play a stressor-specific modulatory role in regulation of HPA function.     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats.

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decreased progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress-induced behavioral depression. Key Words: WKY rats, acute and chronic stress, gender, passive avoidance, open field behavior, stress-ulcer, adrenal weight, serotonin, dorsal raphe nucleus     

Influence of chronic corticosterone and glucocorticoid receptor antagonism in the amygdala on fear conditioning

Glucocorticoid receptor activation within the basolateral amygdala (BLA) during fear conditioning may mediate enhancement in rats chronically exposed to stress levels of corticosterone. Male Sprague-Dawley rats received corticosterone (400 microg/ml) in their drinking water (days 1-21), a manipulation that was previously shown to cause hippocampal CA3 dendritic retraction. Subsequently, rats were adapted to the fear conditioning chamber (day 22), then trained (day 23), and tested for conditioned fear to context and tone (day 25). Training consisted of two tone (20s) and footshock (500 ms, 0.25 mA) pairings. In Experiment 1, muscimol (4.4 nmol/0.5 microl/side), a GABAergic agonist, was microinfused to temporarily inactivate the BLA during training. Rats given chronic corticosterone showed enhanced freezing to context, but not tone, compared to vehicle-supplemented rats. Moreover, BLA inactivation impaired contextual and tone conditioning, regardless of corticosterone treatment. In Experiment 2, RU486 (0, 0.3, and 3.0 ng/0.2 microl/side) was infused on training day to antagonize glucocorticoid receptors in the BLA. Corticosterone treatment enhanced fear conditioning to context and tone when analyzed together, but not separately. Moreover, RU486 (3.0 ng/side) selectively exacerbated freezing to context in chronic corticosterone-exposed rats only, but failed to alter tone conditioning. Serum corticosterone levels were negatively correlated with contextual, not tone, conditioning. Altogether, these suggest that chronic corticosterone influences fear conditioning differently than chronic stress as shown previously. Moreover, chronic exposure to corticosteroids alters BLA functioning in a non-linear fashion and that contextual conditioning is influenced more than tone conditioning by chronic corticosterone and BLA glucocorticoid receptor stimulation.