Stimulation of the prelimbic cortex differentially modulates neuroendocrine responses to psychogenic and systemic stressors

The medial prefrontal cortex is important for normal regulation of stress responses, and is implicated in stress-related affective disease states (e.g. depression). In the current study, we investigated the role of the prelimbic division of the prefrontal cortex in control of responses to psychogenic and systemic stressors (restraint and hypoxia, respectively). Acute stimulation of the prelimbic cortical region with bicuculline methiodide (BMI) caused significant reduction of ACTH and corticosterone responses to restraint and reduced Fos activation of paraventricular nucleus neurons, consistent with a role in central inhibition of acute psychogenic stress responses. In contrast, BMI enhanced corticosterone (but not ACTH) responses to hypoxia via a mechanism suggestive of central PVN drive and enhanced adrenal sensitivity. Acute BMI increased restraint stress-induced Fos activation in known downstream targets of the prelimbic cortex (e.g., the basolateral amygdala and central amygdaloid nuclei), suggesting a connection between modulation of amygdalar signaling and stress inhibition. In contrast, hypoxia caused robust Fos activation in the basolateral and central amygdala, which was not affected by prelimbic BMI injection. The data suggest that the prelimbic cortex stimulation is sufficient to trigger inhibition of the HPA axis to psychogenic stress, but may play a very different role in enhancing HPA responsiveness to physical threats.     

Effects of chronic stress on plasma corticosterone, ACTH and prolactin

Rats were placed in a stressful environment for 24 hr per day and levels of plasma hormones were measured after varying numbers of days in the environment. Rats were habituated to operant chambers placed in sound-attenuated enclosures. Food pellets were available by lever press on a FR1 schedule. After 3 days of habituation, rats in the “stressed” group were trained to pull a ceiling chain to avoid or escape shock. Following training, stress trials, consisting of a consecutive sequence of 5 sec each of a warning light, warning tone and 0.16, 0.32, 0.65, 1.3 and 2.6 mA of footshock, occurred approximately once per 5 min around-the-clock. For the first day, the sequence was terminated when the ceiling chain was pulled. On subsequent days, 90% of all shock presentations could be avoided or escaped by chain pull; the remaining 10% of trials were inescapable and the entire sequence was presented. Control rats lived in identical chambers without presentation of shock. Rats were sacrificed after 1, 2, 3, 4, 7 or 14 days in this environment and levels of plasma corticosterone, ACTH and prolactin were determined. Levels of plasma corticosterone were elevated during the first 7 days in the stressful environment, but returned to control values by day 14. Levels of plasma ACTH and prolactin were similar in stressed and control rats at all time points measured. These data suggest that stress-induced changes in glucocorticoids but not in ACTH or prolactin might mediate some of the physiological changes that occur as the result of chronic stress.     

Role of neuroendocrine pathways in cognitive decline during aging

The pineal and pituitary-adrenocortical secretions play an important role in adaptive responses of the organism acting as coordinating signals for both several biological rhythms and multiple neuroendocrine and metabolic functions.The more relevant neuroendocrine changes occurring with ageing affect the secretion of melatonin and of corticosteroids. These changes may be clearly appreciated by the study of their circadian rhythmicity.The circadian profile of plasma melatonin was clearly flattened in elderly subjects and even more in old individuals with dementia. Indeed, the impairment of melatonin signal occurring in aging was related either to age itself or to the cognitive performances of subjects.The biosynthetic dissociation between glucocorticoids and androgen secretion is responsible for the selective impairment of androgens, such as DHEA and DHEA-S, by comparison to cortisol.Due to the opposite effects of the two kinds of corticosteroids either in the periphery and in the CNS, the imbalance between glucocorticoids and androgens, well demonstrated by the evaluation of the cortisol/DHEA-S molar ratio, may be responsible for the occurrence in the CNS of a more neurotoxic steroidal milieu, already present in clinically healthy elderly subjects and especially in patients with dementia. The effects of that steroidal milieu are more prominent at the level of the hippocampal-limbic structure, involved both in the modulation of endocrine structures, such as the HPA axis, and in the control of cognitive, behavioral and affective functions.     

The pituitary-adrenal response to novel stimulation and ether stress in young adult and aged rats

Pituitary-adrenal responsiveness to stress induced by either psychological (novelty) or physiological (ether) stimuli was examined in young (3 to 6 months) and old (24 to 27 months) male and female rats. In Experiment 1, subjects were placed in a novel environment for 3 min. Blood samples were collected at 0, 15, 30, 45, and 60 min. In Experiment 2, a blood sample was collected from experimental subjects immediately following 15 min in a novel environment; a basal sample was collected from control subjects. In Experiment 3, basal and stress blood samples were collected from subjects exposed to ether vapors. Blood samples were assayed for plasma corticosterone content. The major findings were: (1) no change with age in either sex in basal corticosterone levels or in the time course of the adrenocortical response; (2) no change with age in males in stress-induced increments in corticoids; (3) no change with age in females in corticoid elevations induced by a mild stressor (Experiment 1), but a decrement in elevations induced by more potent stressors (Experiments 2 and 3).     

Effects of treadmill exercise on hypoactivity of the hypothalamo-pituitary-adrenal axis induced by chronic administration of corticosterone in rats

The stress response alters behavior, autonomic function and secretion of multiple hormones, including CRF, ACTH, and glucocorticoid, through the HPA axis. Consecutive stress exposures lead to HPA axis dysregulation such as hyperactivity in Alzheimer's disease and depression, and hypoactivity in post-traumatic stress disorder. In the present study, we established a model of hypoactivated HPA axis in rat through chronic administration of corticosterone (40 mg/kg, s.c.) for 19 consecutive days. In this model, CRF mRNA expression in the hypothalamus and ACTH levels in serum were significantly decreased by chronic administration of corticosterone. In addition, the effect of treadmill exercise was investigated in our hypoactivated HPA axis rat model. Treadmill exercise recovered the dysregulated hypoactivity of the HPA axis induced by corticosterone administration for 19 days. The results of the present study suggest that treadmill exercise may aid recovery of hypoactivated HPA axis dysregulation in psychological diseases such as post-traumatic stress disorder.     

Neuroendocrine effects of stress on immunity in the elderly: implications for inflammatory disease

Age-related changes in immune function leave older adults at risk for a host of inflammatory diseases. Immune-mediated inflammatory processes are regulated by neuroendocrine hormones, including glucocorticoids, dehydroepiandrosterone, and the catecholamines, epinephrine, and norepinephrine. This regulation, however, becomes impaired in older adults in light of age-related changes in endocrine function. Chronic stress shows similarly harmful effects on neuroendocrine and immune function and may, therefore, combine with age to further increase disease risk in older adults. This article highlights evidence for the impact of age and stress on neuroendocrine regulation of inflammatory processes that may substantially increase risk for inflammatory disease at older ages.     

Social status differentiates rapid neuroendocrine responses to restraint stress

Male Anolis carolinensis that win aggressive interactions mobilize neuroendocrine responses to social stress more rapidly than defeated lizards. We initially examined temporal patterns of neuroendocrine response to restraint stress in lizards of unknown status, and then investigated whether winning males respond more rapidly to this non-social stressor. Size-matched male pairs interacted to establish social status, and then were returned to individual home cages for 3 days. Plasma and brains were collected from non-restrained dominants and subordinates, and from a non-interacting control group. Additional groups of dominants and subordinates underwent 90 s restraint stress, with plasma and brains collected either immediately or 300 s after restraint. In lizards of unknown social status restraint stimulated rapid monoaminergic responses in nucleus accumbens, hippocampus, amygdala, and locus ceruleus, with delayed responses seen in VTA and raphé. Non-restrained dominants and subordinates had lower levels of raphé serotonergic activity and lower hippocampal dopaminergic activity 3 days after interacting, compared to controls. Dominants had higher corticosterone levels, both immediately and 300 s after restraint, than either non-restrained dominants or restrained subordinates. Restraint induced higher raphé serotonergic activity in dominants. However, subordinates also showed rapid responses to restraint; exhibiting lower hippocampal dopamine (DA) levels than non-restrained subordinates. At 300 s after the stress, amygdalar serotonin levels increased in dominants, while subordinates showed higher amygdalar DA levels. These results suggest that stressful aggressive interactions will not only alter basal neurochemical activity, but also influence neuroendocrine responses to non-social stressors according to individual social status.     

Effect of chronic restraint stress on carbohydrate metabolism in rat

There is some evidence suggesting that stress may induce diabetes mellitus; the effects of restraint stress however need to be investigated. The present study investigates the role of chronic restraint stress on carbohydrate metabolism in male rats. The animals of the stressed group (n=8) were exposed to different restraint stressors (1 h twice daily) for 30 days. On days 1, 15 and 30, before stress exposure, the animals were weighed and fasting blood samples were obtained by tail snipping and subsequently oral glucose tolerance tests (OGTT) were carried out. Fasting plasma glucose levels on the 15th day and the plasma glucose concentrations, on the 15th and 30th days of the experiment at 15 and 60 min following OGTT, in the stressed group, were significantly higher as compared to the control group. In the stressed group, fasting plasma insulin levels on the 15th and 30th days of the experiment and the plasma insulin concentrations, on the 15th day at 15 and 60 min after performing OGTT, were significantly lower as compared to the control group. Fasting plasma corticosterone concentrations were significantly increased on the 15th day of the experiment in the stressed rats as compared to the control rats and to concentrations on the 1st day. The weights of the stressed rats on the 15th and 30th experimental days were significantly lower than the controls. In conclusion, chronic restraint stress for 30 days leads to low body weight gain in rats and impairs glucose metabolism perhaps by affecting corticosterone and insulin secretion and by inducing a degree of insulin resistance.     

Aging increases basal but not stress-induced levels of corticosterone in the brain of the awake rat

The main purpose of this study was to evaluate the effect of aging on plasma and free corticosterone (CORT) levels in the brain in basal conditions and in response to an acute stressor. Microdialysis experiments were performed in the hippocampus (HC) and the prefrontal cortex (PFC) of young adult (6 months) and aged (24 months) male Wistar rats. Basal free levels of CORT in the HC and the PFC were higher in aged animals. Restraint stress increased plasma CORT and free CORT levels in the HC and the PFC both in young and aged animals. However, while the increase of plasma CORT was higher in aged rats compared with young rats, the increases of free CORT in the HC and the PFC were not different between these two groups of rats. These results suggest that the changes produced by aging in the brain may be related to the enhanced basal levels of free CORT and not to the CORT increases in response to stress.     

Cardiovascular, sympathetic and adrenal cortical responsiveness of aged fischer-344 rats to stress

While resting, Fischer-344 rats underwent a decrease in heart rate and an increase in diastolic blood pressure and plasma norepinephrine with increasing age. The blood pressure of adult rats increased significantly during a 3 minute immobilization. The blood pressure of old rats failed to increase during stress, decreased to below control level immediately following the termination of stress and they died within 24 hours. Three minutes of stress failed to increase the heart rate of old rats while 30 min of stress produced a small increase in the heart rate, approximately $\text{sol1}\text{3}$ to $\text{sol1}\text{2}$ of the increase seen in younger rats. The old rats showed no decrease in the maximal adrenergic medullary or cortical responses to stress, but they had a prominent 3 min delay in the maximal peak of norepinephrine release. The 30 minute stress caused a greater increase in plasma epinephrine in old rats than in adult rats while it initiated a decrease in beta-adrenergic responses such as heart rate and plasma glucose. The present results indicate that old rats lose their ability to cope with acute stress due to decreased adrenergic responsiveness and increased “shock” reaction.     

Binge-type eating attenuates corticosterone and hypophagic responses to restraint stress

Binge eating has been associated with stress responses. Data in rats suggest that activation of the hypothalamic-pituitary-adrenal (HPA) axis is suppressed by consumption of a high sucrose diet, and is increased with exposure to a high fat diet. Additionally, the choice to consume a highly palatable food following exposure to a stressor results in reduced corticosterone levels. To test the effects of intermittent access to a high sugar/high fat food on stress hormone levels, rats were given either unrestricted (UR) access to a sucrose-vegetable shortening mixture (SVS) or 2 hour SVS access 7 days (7D) or 3 days (3D) per week for 4 weeks. Rats on the UR and 3D schedules consumed significantly more calories per day than did controls with no access to SVS, and the 7D and 3D rats consumed as many SVS calories in the 2 hour access period as did the UR rats with 24 hour access to SVS. After 4 weeks of access to SVS (UR, 7D, and 3D), rats were briefly restrained. Control and UR rats had elevated corticosterone during and following restraint, whereas there were no differences in corticosterone levels of 7D and 3D rats in response to restraint, as compared to baseline. Post-restraint consumption of chow was significantly decreased in all groups, and consumption of SVS was reduced in the UR, but not the 7D and 3D rats. These data demonstrate that intermittent access to SVS dampens the corticosterone response to restraint stress and that stressful events do not induce bingeing in non-bingeing animals with access to a high sucrose/high fat food.     

Cardiovascular, sympathetic and adrenal cortical responsiveness of aged fischer-344 rats to stress

While resting, Fischer-344 rats underwent a decrease in heart rate and an increase in diastolic blood pressure and plasma norepinephrine with increasing age. The blood pressure of adult rats increased significantly during a 3 minute immobilization. The blood pressure of old rats failed to increase during stress, decreased to below control level immediately following the termination of stress and they died within 24 hours. Three minutes of stress failed to increase the heart rate of old rats while 30 min of stress produced a small increase in the heart rate, approximately to of the increase seen in younger rats. The old rats showed no decrease in the maximal adrenergic medullary or cortical responses to stress, but they had a prominent 3 min delay in the maximal peak of norepinephrine release. The 30 minute stress caused a greater increase in plasma epinephrine in old rats than in adult rats while it initiated a decrease in beta-adrenergic responses such as heart rate and plasma glucose. The present results indicate that old rats lose their ability to cope with acute stress due to decreased adrenergic responsiveness and increased “shock” reaction.     

Some relationships between adrenal function and the effectiveness of a period of isolation in inducing intermale aggression in albino mice

Because an inverse relationship has been demonstrated by numerous authors between aggressiveness and adrenal function in rodents, a series of experiments, in which manipulations of the pituitary/adrenal axis were carried out, was undertaken to determine whether this had any modulating influence on fighting behavior. The effects of adrenalectomy, dexamethasone blocking of the pituitary and of ACTH injection on isolation-induced aggression in the immature, naive and the mature, sexually experienced male albino laboratory mouse are described. It was found that whilst adrenalectomy reduced aggression, dexamethasone blocking enhanced it and ACTH injection reduced it, although the differences were not always significant. The possible mode of action of ACTH in reducing aggression and the consequences to natural populations of rodents is discussed.     

Effect of acute stress and gender on isatin in rat tissues and serum

Isatin is an endogenous indole present in mammalian tissues and fluids. This study was designed to test the effect of both acute stress (AS) and gender on isatin's levels in rat serum, heart and brain, using a HPLC-UV detection method. Basal brain isatin levels were higher in females than in males. AS resulted in increased isatin levels in male serum, heart and brain, and in female serum and heart, but not in the brain. The percentage increases were greater in males than in females in all three sources. After stress, there were significant correlations between isatin levels in the serum and the heart. However, there were no correlations between brain levels and those in the other sources. These results consolidate previous evidence that isatin levels are altered by stress and suggest that brain isatin is under separate control from that in the periphery.     

Genetic influences on behavioral and neuroendocrine responses to predator-odor stress in rats

The exposure of animals to a variety of stressful events can induce behavioral and physiological responses, which can be modulated by anxiety levels. It is well recognized that genetic factors play a substantial role in both anxiety and stress reactivity. The present study examined the effect of exposure to 2,4,5-trimethylthiazoline (TMT), a component of fox feces, on nociception and corticosterone levels in Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rat strains (which display genetic differences in anxiety models such as the elevated plus-maze and open-field). The influence of two quantitative trait loci (QTL), named Ofil1 and Ofil2, which are known to affect emotionality in LEW versus SHR intercrosses on the responses to TMT was also investigated. LEW and SHR rats of both sexes displayed similar levels of behavioral and neuroendocrine responses after TMT exposure. As expected, TMT odor stress produced analgesia and enhanced corticosterone levels. Ofil1 on chromosome 4 affected stress-induced analgesia in males only. Ofil2 on chromosome 7 had no effect. The results suggest that behaviors measured in classical models of generalized anxiety and reactivity to stress produced by predator odors can be genetically dissociated. Finding a locus with an effect on the behavioral responses to stress represents the starting point in the search for genes responsible for stress-related traits.     

Dysregulated physiological stress systems and accelerated cellular aging

Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6, c-reactive protein, tumor necrosis factor-alpha), hypothalamic-pituitary-adrenal-axis indicators (salivary cortisol awakening curve [area under the curve indicators, with respect to the ground and increase], evening levels, 0.5 mg dexamethasone cortisol suppression ratio), and autonomic nervous system measures (heart rate, respiratory sinus arrhythmia, pre-ejection period) were determined. Linear regression analyses were performed and adjusted for sociodemographic, lifestyle and clinical factors. Shorter LTL was significantly associated with higher c-reactive protein, interleukin-6, area under the curve with respect to increase, and heart rate. A cumulative index score was calculated based on the number of highest tertiles of these 4 stress markers. LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively.     

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus–pituitary–adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.     

氧化低密度脂蛋白通过氧化应激诱导小鼠造血干细胞衰老

 目的 探讨氧化低密度脂蛋白（ox-LDL）体外诱导造血干细胞(HSCs)衰老的可能机制。方法 用免疫磁性分选法分离纯化小鼠HSC,与ox-LDL共培养,采用β-半乳糖苷酶（SA-β-Gal）染色检测衰老HSC,流式细胞术检测HSC细胞周期分布,混合集落培养(CFU-Mix)检测HSC混合集落形成能力。流式细胞术和免疫荧光检测HSC产生活性氧（ROS）的量,酶学比色法检测HSC培养上清液超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）及丙二醛（MDA）含量。Southern blot和TRAP-PCR法检测HSC端粒长度和端粒酶活性。结果 ox-LDL诱导HSC呈现典型的衰老生物学表现：SA-β-Gal染色阳性细胞率显著增高（P <0.01）; G0/G1 期比例明显增加,S 期显著减少（P <0.01） ;CFU-Mix数量显著减少（P <0.01）。衰老HSC端粒缩短（P <0.05）,端粒酶活性降低（P <0.05）。衰老HSC ROS含量显著增加（P <0.01）,细胞培养上清液中SOD、GSH-Px活力下降、 MDA含量增加（P <0.05）。 结论 ox-LDL能通过氧化应激诱导HSC衰老,其机制可能与ROS的蓄积及抗氧化酶活性受抑引起端粒功能异常有关。     

Effects of cold stress on tumor growth

The relationship between stress and tumor growth was assessed in experiments in which the paradigm was held constant while type of tumor and sex of rats were varied. Singly housed male and female W/Fu rats were given cold stress before and/or after injection of tumor cells, or received no stress at all. Rats stressed only before receiving the tumor cells developed significantly smaller tumors than the nonstressed control group. Tumors of the other two groups were only slightly smaller than those of the nonstressed control group. The results are interpreted to indicate that being stressed before disease may provide an inoculation effect, whereas stress occurring after disease onset (or no stress at all) precludes to increased severity of the illness.     

Differential corticosterone responses to stress in the lung in two strains of Flinders rats

Background Acute stress affects a variety of organs and cellular systems. These include the hypothalamic–pituitary–adrenal (HPA) axis, corticotropin‐releasing factor (CRF), mast cells and nerves. Flinders‐sensitive (FSL) rat strains have hypercholinergic responses and are more sensitive than Flinders‐resistant rats (FRL) to anaphylaxis. Objective To investigate the effects of acute water avoidance stress (1 h) on FSL and FRL tracheal epithelial tissue. Methods We measured short circuit current (I_sc) as a measure of tracheal response, and the effect of substance P (SP) on tracheal epithelium in Ussing chambers. Electron microscopy was performed to assess mast cell activation. Results Both strains showed increased I_sc responses to stress, inhibited by prior injection of the CRF receptor 1 and 2 antagonist, α‐helical CRF‐(9–41). No increases in conductance were seen. Stress responses were accompanied by electron microscopic morphologic evidence for mast cell degranulation, which was not completely inhibited by α‐helical CRF‐(9–41) pre‐treatment. Stress primed the epithelium for an enhanced response to SP in FSL, but this again was not inhibited by α‐helical CRF‐(9–41). FRL had 2.5 times the corticosterone response of FSL. Conclusion Acute stress affects the tracheal epithelium, not accompanied by changes in ion permeability, but associated with mast cell degranulation. Because blunted HPA axis responses are associated with vulnerability to inflammation, this may partially explain the findings. These stress effects on the lung have a genetic basis associated with relative corticosterone responses, are complex and only in part mediated by CRF.