Neonatal asphyxia under hyperthermic conditions alters HPA axis function in juvenile rats

Neonatal anoxia is an example of early-life threatening experience that might exert long-lasting behavioral disturbance. One of the consequences of neonatal asphyxia is hyperactivity in open-field test. Changes in open-field activity are coupled with changes in the function of the hypothalamic–pituitary–adrenal (HPA) axis. A critical determinant of the severity of hypoxic–ischemic brain injury in newborn rats is body temperature. Hyperthermia under anoxic conditions increases locomotor activity in the open-field test. Therefore, the aim of the present study was to test whether body temperature during neonatal anoxia can affect basal and stress-induced corticosterone secretion in rats. At the age of 2 days Wistar rat pups were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 °C (typical for the rat pups), or was elevated to a level typical for febrile adults (39 °C). Control rats were exposed to atmospheric air under the respective thermal conditions. Basal and stress-induced corticosterone levels were assessed using sulphuric acid-induced fluorescence, on postnatal day 14. Body temperature during neonatal asphyxia altered the early developmental profile of plasma corticosterone. Hyperthermia under anoxic conditions decreased the corticosterone response to open-field stress. In conclusion, febrile body temperature changes corticosterone release, which might induce neurobehavioral disturbances. On the other hand, a protection against the HPA dysfunction can be achieved by the reduced physiological neonatal body temperature.     

Effects of neonatal corticosterone treatment on maze performance and HPA axis in juvenile rats.

Previous research has indicated that administering corticosterone to dams' drinking water for 21 days produced persistent alterations in physiology and behavior. We investigated whether 4 days of corticosterone exposure would have similar effects, and whether greater effects would be found when corticosterone was administered early in neonatal life than later in neonatal life. Sprague-Dawley dams were given either corticosterone (250 microg/ml) in their water bottles for postnatal days (PND) 5-9 (early corticosterone treatment: ECT), PND 13-17 (late corticosterone treatment: LCT) or no treatment (NT). At the end of treatment, corticosterone levels were higher in pups of corticosterone drinking dams. However, at weaning, ECT and LCT pups had lower basal corticosterone levels than NT pups. As juveniles, ECT pups learned to navigate to a visible and then to a nonvisible platform in a Morris water maze more quickly than did LCT and NT pups. Among females, ECT pups had higher corticosterone release in response to stress than LCT and NT pups. There were no differences in hippocampal corticosteroid receptor levels among the groups. The pattern of results is similar to, but not identical to, that found for pups exposed to corticosterone for 21 days. The results also suggest that there is a critical or sensitive period for corticosterone treatment in that early treatment was more effective than later treatment.     

Fractionation of phasic responses in a dishabituation paradigm

The evoked cardiac response (ECR) of heart rate deceleration, the skin resistance response (SRR), respiratory pause, and the peripheral pulse amplitude response (PPAR) of vascular constriction were examined in 30 subjects using a dishabituation paradigm. Ten trials of one stimulus magnitude were followed by an interpolated change trial of a different magnitude, and five trials of the orginal magnitude. Results indicated that ECR was consistent in amplitude, failing to reflect any aspect of stimulus manipulation, PPAR behaved as an absolute indicator of stimulus magnitude and respiratory pause reflected stimulus novelty. SRR exhibited stimulus novelty and magnitude effects, recovery to the change stimulus and dishabituation with the following stimuli. These results are incompatible with unitary OR theory and provide support for an alternative multi-register theory of preliminary processes in OR elicitation.     

Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: Evidence for impaired inhibitory control of the HPA axis in heavy drinkers.

Alcoholism and heavy drinking are associated with a number of physiological, behavioral, affective, and cognitive problems. One such problem involves dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, with alcoholics showing higher basal cortisol levels and reduced inhibitory feedback control. In addition, alcohol consumption is associated with decreased heart rate variability (HRV). In the present study we examined the relationships among alcohol consumption, cortisol excretion, and HRV in 542 apparently healthy men. Men in the top tertile of self-reported alcohol consumption had higher cortisol levels and lower HRV compared to men in the lower two tertiles of alcohol consumption. In addition, the inverse relationship between cortisol and HRV was greatly attenuated in the heavy drinking group even after accounting for a number of potential confounding factors. These results support prior research on the HPA axis dysregulation in alcoholics and suggest impaired inhibitory control of the HPA axis in heavy drinkers. The findings are consistent with the neurovisceral integration model, which links central and peripheral processes, and may provide a comprehensive framework for the future investigation of the complex mix of physiological, behavioral, affective, and cognitive factors which comprise the heavy drinking phenotype.     

Differential cardiovascular responses to stressors in hypertensive and normotensive rats

The aim of this study was to determine to what extent stress-induced cardiovascular responses depend upon rat strain and/or stressor. Spontaneously hypertensive rats (SHRs), Wistar-Kyoto rats (WKYs) and Sprague-Dawley (SD) rats were implanted with telemetry probes in order to measure heart rate and blood pressure changes when exposed to a stressor. The stress protocols employed included handling, air-jet and restraint, where each stressor was repeated over 10 consecutive days. In addition, a heterologous protocol was established whereby the experimental groups having experienced 10 days of air-jet stress were then immediately exposed to 10 consecutive days of restraint. Each stressor caused graded tachycardic and pressor responses in all strains. For all strains, the magnitude and duration of heart rate and blood pressure increases were greatest in the restraint-based protocols while handling and air-jet caused submaximal changes. A comparison between strains indicated that SHRs exhibited prolonged pressor responses to each of the stressor types tested as compared to the normotensive strains. In addition, repeated exposure over 10 days to handling and air-jet in SHRs caused tachycardic and/or pressor responses to adapt to 'normotensive-like' levels. Heterologous restraint stress caused sensitization of cardiovascular responses upon first exposure, predominantly in normotensive strains. Collectively these data show that the magnitude and duration of the tachycardia and pressor responses evoked by the stressors were different within the strains and were also modified by prior experience. In addition, the cardiovascular profiles presented in this study demonstrate that, within each strain, the heart rate response during stress is graded according to the type of stressor encountered.     

"Snacking" causes long term attenuation of HPA axis stress responses and enhancement of brain FosB/deltaFosB expression in rats

A history of limited, intermittent intake of palatable food (sucrose drink) attenuates hypothalamic-pituitary-adrenal (HPA) axis stress responses and induces markers of neuronal plasticity in stress- and reward-regulatory brain regions. Synaptic plasticity could provide a mechanism for long-term changes in neuronal function, implying that sucrose stress-dampening may endure over long periods of time. The present study tests the persistence of HPA axis dampening and plasticity after cessation of palatable drinking. Adult, male Long-Evans rats (n = 10-13) with free access to water and chow were given additional twice-daily access to 4 ml sucrose (30%) or water for 14 days. Rats were subsequently tested for HPA responsiveness to an acute (20 min) restraint stress at 1, 6 and 21 days after the cessation of sucrose. Brains were collected for immunohistochemical analysis of FosB/deltaFosB, a marker of long-term neuronal plasticity, in the basolateral amygdala (BLA) and nucleus accumbens (NuAc). Prior sucrose consumption significantly decreased the plasma corticosterone response to restraint at 1 day after the last palatable drink presentation, and also increased FosB/deltaFosB-positive cells in the BLA and in the NuAc core. This HPA-dampening persisted through 21 days after the termination of the palatable drink, as did the increased FosB/deltaFosB immunoreactivity in both the BLA and the NuAc core. These data suggest that chronic palatable food intake causes lasting changes in stress/reward-modulatory circuitry and that the suppressed hormonal response to stress that can persist well beyond periods of palatable drink exposure.     

Sex differences in HPA axis activity in response to a meal

BackgroundSex may influence the relationship between HPA axis functioning and obesity. This has been suggested to be due to sex-specific differences in body composition, body fat distribution and psychological variables. Age and the use of oral contraceptives may also influence the relationship between HPA axis functioning and obesity.ObjectiveTo systematically investigate whether body composition, body fat distribution, psychological variables, age, or possible oral contraceptive use contribute to sex differences in HPA axis activity in response to a meal.MethodsSubjects were men (n = 19) and women (n = 19) between 18 and 51 years old with BMI between 20.3 and 33.2 kg/m². HPA axis activity was measured by salivary free cortisol levels before consuming a meal, and at 45, 75 and 125 min postprandial on four repeated test days. Anthropometric and body composition measurements were performed. Questionnaires were used to assess cognitive eating behavior and trait anxiety level.ResultsNo differences between the test days in postprandial cortisol responses appeared. Responses were significantly higher in men compared with women (p < .05). No significant correlations were found between cortisol concentrations and sex-specific body composition or body fat distribution. Psychological variables did not contribute to differences in cortisol responses after a meal between men and women. In women, baseline cortisol concentrations correlated inversely with age (p = .024).ConclusionHigher HPA axis activity following a meal in men vs. women remained irrespective of sex-specific differences in body composition, body fat distribution, psychological variables, or in age. In women baseline cortisol concentrations were age-dependent.     

Circadian phase and sex effects on depressive/anxiety-like behaviors and HPA axis responses to acute stress

Circadian dysregulation in sleep pattern, mood, and hypothalamic-pituitary-adrenal (HPA) axis activity, often occurring in a sexually dimorphic manner, are characteristics of depression. However, the inter-relationships among circadian phase, HPA function, and depressive-like behaviors are not well understood. We investigated behavioral and neuroendocrine correlates of depressive/anxiety-like responses during diurnal (‘light’) and nocturnal (‘dark’) phases of the circadian rhythm in the open field (OF), elevated plus maze (EPM), forced swim (FST), and sucrose contrast (SC) tests. Plasma corticosterone (CORT) was measured after a) acute restraint and OF testing and b) FST. Both phase and sex significantly influenced behavioral responses to stress. Males were more anxious than females on the EPM in the light but not the dark phase. Further, the open:closed arm ratio was lower in the dark for females, but not males. By contrast, in the FST, females showed more “despair” (immobility) when tested in the dark, while phase did not affect males. Acute restraint stress increased OF activity in the light, but not the dark, phase. CORT levels were increased in both sexes following the FST, and in males and light phase females post-OF. As expected, females had higher CORT levels than males, even at rest, and this effect was more pronounced in the dark phase. Together, our data highlight the sexually dimorphic influences of circadian phase and stress on behavioral and hormonal responsiveness.     

安神解郁汤对CUMS大鼠海马p-Tau及HPA轴的影响

目的:观察安神解郁汤(ASJYD)对抑郁大鼠海马微管蛋白p-Tau及下丘脑-垂体-肾上腺(HPA)轴的影响。方法:雄性SD大鼠40只分为对照组(Control)、抑郁模型组(CUMS)和ASJYD治疗组(ASJYD),利用慢性不可预测轻度应激(CUMS)建立抑郁大鼠模型,通过灌胃方法给予抑郁大鼠ASJYD治疗;通过糖水偏好实验、旷场实验和Morris水迷宫测试各组大鼠的行为学表现; HE染色观察海马组织结构的变化;用Western Blot方法检测大鼠海马组织中p-Tau的表达水平; ELISA检测大鼠下丘脑促肾上腺皮质激素释放因子(CRF)和血清促肾上腺皮质激素(ACTH)变化。结果:糖水消耗和糖水偏好百分比模型组低于对照组和药物治疗组(P 0. 01)。旷场实验中行走路程、中央格时间、站立次数和修饰行为模型组低于对照组和药物治疗组(P 0. 01)。水迷宫平均逃避潜伏期模型组高于对照组和药物治疗组(P 0. 01)。HE染色各组海马组织结构发生显著变化。模型组大鼠海马p-Tau蛋白的表达低于对照组,用药治疗后显著提高(P 0. 01)。模型组下丘脑CRF含量和血清ACTH水平明显高于对照组,治疗后有明显改善(P 0. 01)。结论:安神解郁汤对CUMS大鼠抗抑郁作用,可调节p-Tau以及下丘脑CRF和血清ACTH的变化。     

Functional role of local GABAergic influences on the HPA axis

Neuronatomical and pharmacological studies have established GABA-mediated inhibition of the HPA axis at the level of the PVN. The origin of this innervation is a series of local hypothalamic and adjacent forebrain regions that project to stress-integrative hypophysiotropic CRH neurons. While a role in tonic inhibition of the stress axis is likely, this system of inhibitory loci is also capable of producing a dynamic braking capacity in the context of the neuroendocrine stress response. The latter function is mediated in large part by glutamatergic forebrain afferents that increase GABA release at the level of the PVN. In addition, this local GABA system can be inhibited by upstream GABAergic projection neurons, producing activation of the HPA axis via removal of GABAergic tone. This PVN projecting GABA network interfaces with a wide range of homeostatic mechanisms, and is capable of biochemical plasticity in response to chronic stress. Collectively, the elements of this system provide for exquisite control of neuroendocrine activation in the face of stressful stimuli, and loss of this regulatory capacity may underlie many stress-related disorders.     

HPA轴相关的帕金森病与骨质疏松症的共病机制研究进展

帕金森病 （Parkinson''s Disease,PD） 是骨质疏松症的独立风险因素。PD合并骨质疏松患者在临床上数量较多, 预后较差,给患者生活和公共卫生带来极大的负担。然而,目前依然缺乏对PD与骨质疏松共病机制的探索,为疾病的防治带来困难。下丘脑-垂体-肾上腺轴 （Hypothalamic-Pituitary-Adrenal axis,HPA） 活性异常在 PD患者中已有多年的研究,被认为参与了 PD 的发病机制。HPA 轴的激活与慢性压力相关,并且可以导致血浆皮质醇、糖皮质激素等固醇类激素水平上升。而慢性压力应激已被报道可以导致骨质流失,且糖皮质激素在临床上的应用也被认为与骨质疏松有关。这提示HPA轴的活性异常可能是PD共患骨质疏松症的重要机制。本综述针对PD患者中的HPA轴活性功能异常的病理过程,提出HPA轴活性异常可能通过导致固醇类激素水平异常上升、甲状旁腺激素水平异常以及交感神经系统异常三个方面影响骨代谢水平, 对PD和骨质疏松共患机制进行探索,以期为临床上PD患者的治疗提供线索和启示。     

Adrenocortical, beta-endorphin and behavioral responses to graded stressors in differentially reared rats

Isolation rearing has long been suspected to alter hormonal and behavioral responses to stress. Two experiments were conducted to test the hypothesis that isolates are more timid or fearful than socially reared rats when exposed to novel test environments. In both, isolate response to 3 graded stressors was compared to that of socially-reared rats. In the first experiment, animals were handled, shocked or not treated prior to testing to produce three levels of conditioned fear. They were then tested on four paradigms previously shown sensitive to conditioned fear: open field activity, emergence latency, auditory startle, and latency to accept food from the experimenter. In the second experiment, rats were given a 0-, 5- or 20-min forced swim, then sacrificed for analysis of plasma corticosterone and pituitary and hypothalamic beta-endorphin. It was found that isolates showed little evidence of enhanced behavioral timidity, although rearing effects were seen on all 4 behavioral measures. Plasma corticosterone levels increased in a graded fashion over the course of the forced swim, but there was no effect of rearing conditions. While there were no effects of rearing or stress on hypothalamic beta-endorphin, pituitary beta-endorphin content was lower in females than in males, and isolate males had lower pituitary endorphin than social males. In summary, these experiments provide no evidence that isolation rearing produces a primary, global increase in fearfulness, but identify several behavioral and hormonal differences associated with differential housing in rats.     

N-methyl-d-aspartate enhancement of phasic responses in primate neocortex

 In area 17 of the awake macaque, disinhibition by blockade of GABA_A receptors results in a marked elevation in neuronal excitability, with a particular focus in the supragranular laminae. We examined the possibility that the excitatory supragranular response is N-methyl-d-aspartate (NMDA)-mediated. Laminar activity profiles consisting of flash-evoked field potential, current source density (CSD) and multiunit activity (MUA) measures were obtained during striate cortex penetrations using multicontact electrodes that incorporated single or double microinjection cannulae. Profiles were recorded before and at successive time points after bicuculline induction of disinhibition. Both the noncompetitive NMDA antagonist MK-801 and the competitive antagonist APV reversed bicuculline effects, producing a normal laminar activity profile. NMDA-mediated enhancement of excitatory responses in the supragranu- lar laminae of neocortex is believed to play a role in normal signal processing, as well as in epileptic manifestations. Received: 10 March 1996 / Accepted: 1 October 1996     

Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli

Exposure to stress can result in an increased risk for psychiatric disorders, especially among genetically predisposed individuals. Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia and is also associated with psychotic bipolar disorder. In the rat, the neurons of the hypothalamic paraventricular nucleus show strong expression of Nrg1 mRNA. In patients with schizophrenia, a single nucleotide polymorphism in the 5′ region of NRG1 interacts with psychosocial stress to affect reactivity to expressed emotion. However, there is virtually no information on the role of NRG1 in hypothalamic-pituitary-adrenal axis function, and whether the protein is expressed in the paraventricular nucleus is unknown. The present studies utilize a unique line of Nrg1 hypomorphic rats (Nrg1^Tn) generated by gene trapping with the Sleeping Beauty transposon. We first established that the Nrg1^Tn rats displayed reduced expression of both the mRNA and protein corresponding to the Type II NRG1 isoform. After confirming, using wild type animals, that Type II NRG1 is expressed in the neurocircuitry involved in regulating hypothalamic-pituitary-adrenal axis responses to environmental stimuli, the Nrg1^Tn rats were then used to test the hypothesis that altered expression of Type II NRG1 disrupts stress regulation and reactivity. In support of this hypothesis, Nrg1^Tn rats have disrupted basal and acute stress recovery corticosterone secretion, differential changes in expression of glucocorticoid receptors in the pituitary, paraventricular nucleus and hippocampus, and a failure to habituate to an open field. Together, these findings point to NRG1 as a potential novel regulator of neuroendocrine responses to stress as well as behavioral reactivity.     

Long-term effects of prenatal stress on HPA axis activity in juvenile rhesus monkeys

The effect of stress to the pregnant mother on hormonal responses of the offspring to stressful events was investigated in juvenile rhesus monkeys. Six pregnant monkeys were repeatedly removed from their home cages and exposed to unpredictable noise during mid- to late gestation (Days 90–145 postconception), while six undisturbed pregnant mothers served as controls. Blood samples were collected from the juvenile offspring under anesthesia on four occasions and assayed for ACTH and cortisol. In a second experiment, blood samples were collected from the awake offspring under a baseline and four progressively stressful conditions. Offspring of stressed mothers showed higher ACTH and cortisol levels than control offspring at all four anesthesia samples and at a nonanesthesized home cage baseline. Prenatally stressed offspring also showed higher ACTH values in all four stress conditions. Cortisol values were similar for the two groups under the stress conditions. The disparity between the two groups in the relationship between ACTH and cortisol was greatest in the most stressful condition, suggesting regulatory differences between the two groups. These results indicate that offspring of primate mothers stressed during pregnancy show enhanced HPA axis responsivity to stressors later in life, and concur with rodent findings indicating that prenatal stress may have long-term effects on HPA axis regulation. © 1994 John Wiley & Sons, Inc.     

Evidence for a cephalic site of action of high magnetic fields on the behavioral responses of rats

Static high magnetic fields (MFs) from 7 T to 9 T can elicit behavioral responses in rodents such as suppression of rearing, locomotor circling, and acquisition of a conditioned taste aversion (CTA). MF exposure also induces c-Fos expression in the visceral and vestibular nuclei of the brainstem, suggesting the stimulation of some sensory pathways. It is not clear, however, if the effects of the MF are caused by exposure to the uniform maximal field at the center of the magnet, or by exposure to the steep field gradients along the bore of the magnet during the rat's placement. In addition, the site of action within the rat is unknown. In an attempt to limit MF exposure to rostral or caudal portions of the rats' body, we exposed male and female rats at different positions within the bore of a 14.1-T superconducting magnet ranging from 2 cm (1.6 T at the head) to 155 cm (0.05 T at the head), with the center of the bore at 65 cm (14.1 T across the whole body). This approach also allowed us to expose rats to the maximal field strength (14.1 T) vs. the maximal field gradients (54 T/m). To assess both immediate and delayed behavioral effects, locomotor and CTA responses were recorded. A small but significant CTA was seen after exposure of the head to the lowest MF tested (0.05 T at 155 cm). Graded effects were seen, however, with greater circling and CTA acquisition as the MF strength increased at the rostral end of the rat. This suggests a cephalic site of action. Furthermore, maximal circling and CTA were induced after exposure to the uniform center field, and not after exposure to high field gradients on either side of the center. This suggests that the behavioral responses seen after MF exposure are a consequence of the uniform static field at the center of the magnet, and are not caused by passage through, or exposure to, the vertical field gradients. Female rats responded similarly to male rats, although magnet-induced CTA appeared resistant to extinction in female rats.     

Evidence for a GABAergic inhibitory nigrotectal pathway in the rat

The aim of the present study was to test the GABAergic nature of the inhibitory projection from substantia nigra, pars reticulata (SNr) to superior colliculus (SC) in the rat, through the use of extracellular recordings and microiontophoresis. The effect of SN stimulation on the spontaneous or glutamate-evoked firing of SC units was analyzed. Among 28 SC cells inhibited by SNr stimulation, 27 decreased their firing rate following iontophoretic application of either GABA or glycine. The effect of the iontophoretic administration of bicuculline on SNr-evoked inhibition was studied on 14 of these GABA- and glycine-sensitive neurons. Bicuculline reversibly blocked nigral inhibition on 12 neurons, with iontophoretic current which did not affect glycine depression.These results are consistent with the hypothesis that GABA is the inhibitory transmitter of the nigrotectal projection.