Genetic differences in hippocampal synaptic plasticity

Synaptic plasticity is considered a physiological substrate for learning and memory [Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136] that contributes to maladaptive learning in drug addiction [Schoenbaum G, Roesch MR, Stalnaker TA (2006) Orbitofrontal cortex, decision-making and drug addiction. Trends Neurosci 29:116–124]. Many studies have revealed that drug addiction has a strong hereditary component [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35–69; Uhl GR (2004) Molecular genetic underpinnings of human substance abuse vulnerability: likely contributions to understanding addiction as a mnemonic process. Neuropharmacology 47 (Suppl 1):140–147], however the contribution of the genetic background to drug-induced changes in synaptic plasticity has been scarcely studied. The present study reports on an analysis of long-term potentiation (LTP) and depotentiation in Lewis (LEW) and Fischer-344 (F344) rats, two inbred rat strains that show different proneness to drugs of abuse and are considered an experimental model of genetic vulnerability to addiction [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35–69]. The induction of saturated-LTP was similar in LEW and F344 rats treated with saline or cocaine. However, only slices from LEW saline-treated rats showed the reversal of LTP; thus, the depotentiation of saturated-LTP was not observed in cocaine-injected LEW rats and in F344 animals (treated either with cocaine or saline). These results suggest significant differences in hippocampal synaptic plasticity between Lewis and Fischer 344 rats.     

Exploration of the hypothalamic-pituitary-adrenal function as a tool to evaluate animal welfare

Measuring HPA axis activity is the standard approach to the study of stress and welfare in farm animals. Although the reference technique is the use of blood plasma to measure glucocorticoid hormones (cortisol or corticosterone), several alternative methods such as the measurement of corticosteroids in saliva, urine or faeces have been developed to overcome the stress induced by blood sampling itself. In chronic stress situations, as is frequently the case in studies about farm animal welfare, hormonal secretions are usually unchanged but dynamic testing allows the demonstration of functional changes at several levels of the system, including the sensitization of the adrenal cortex to ACTH and the resistance of the axis to feedback inhibition by corticosteroids (dexamethasone suppression test). Beyond these procedural aspects, the main pitfall in the use of HPA axis activity is in the interpretation of experimental data. The large variability of the system has to be taken into consideration, since corticosteroid hormone secretion is usually pulsatile, follows diurnal and seasonal rhythms, is influenced by feed intake and environmental factors such as temperature and humidity, age and physiological state, just to cite the main sources of variation. The corresponding changes reflect the important role of glucocorticoid hormones in a number of basic physiological processes such as energy metabolism and central nervous system functioning. Furthermore, large differences have been found across species, breeds and individuals, which reflect the contribution of genetic factors and environmental influences, especially during development, in HPA axis functioning. Usually, these results will be integrated with data from behavioral observation, production and pathology records in a comprehensive approach of farm animal welfare.     

From Malthus to motive: how the HPA axis engineers the phenotype, yoking needs to wants

The hypothalamo–pituitary–adrenal (HPA) axis is the critical mediator of the vertebrate stress response system, responding to environmental stressors by maintaining internal homeostasis and coupling the needs of the body to the wants of the mind. The HPA axis has numerous complex drivers and highly flexible operating characterisitics. Major drivers include two circadian drivers, two extra-hypothalamic networks controlling top-down (psychogenic) and bottom-up (systemic) threats, and two intra-hypothalamic networks coordinating behavioral, autonomic, and neuroendocrine outflows. These various networks jointly and flexibly control HPA axis output of periodic (oscillatory) functions and a range of adventitious systemic or psychological threats, including predictable daily cycles of energy flow, actual metabolic deficits over many time scales, predicted metabolic deficits, and the state-dependent management of post-prandial responses to feeding. Evidence is provided that reparation of metabolic derangement by either food or glucocorticoids results in a metabolic signal that inhibits HPA activity. In short, the HPA axis is intimately involved in managing and remodeling peripheral energy fluxes, which appear to provide an unidentified metabolic inhibitory feedback signal to the HPA axis via glucocorticoids. In a complementary and perhaps a less appreciated role, adrenocortical hormones also act on brain to provide not only feedback, but feedforward control over the HPA axis itself and its various drivers, as well as coordinating behavioral and autonomic outflows, and mounting central incentive and memorial networks that are adaptive in both appetitive and aversive motivational modes. By centrally remodeling the phenotype, the HPA axis provides ballistic and predictive control over motor outflows relevant to the type of stressor. Evidence is examined concerning the global hypothesis that the HPA axis comprehensively induces integrative phenotypic plasticity, thus remodeling the body and its governor, the brain, to yoke the needs of the body to the wants of the mind. Adverse side effects of this yoking under conditions of glucocorticoid excess are discussed.     

Hypothalamus-pituitary-adrenal modifications consequent to chronic stress exposure in an experimental model of depression in rats

The modifications in the hypothalamus-pituitary-adrenal (HPA) axis function induced by repeated unavoidable stress exposure, according to a standardized procedure used for inducing an experimental model of depression, were studied. Rats exposed to this procedure show hyporeactivity to both pleasurable and aversive stimuli and this condition is antagonized by the repeated administration of classical antidepressant drugs. We also studied whether imipramine administration during stress exposure would interfere with the possible modifications in the HPA axis. Rats were exposed to a 4-week stress procedure with and without imipramine treatment and then tested for escape, as compared with non-stressed control animals. Twenty-four hours later all rats were bled through a tail nick for plasma corticosterone measurement before and after dexamethasone (10 microg/kg) or corticotropin-releasing hormone (CRH, 1 microg/kg) administration. Rats were then killed, adrenals and thymus weighed, brain areas dissected out and frozen for glucocorticoid receptors (GRs) and corticotropin-releasing hormone receptor 1 (CRHR1) immunoblotting and for the assessment of hypothalamic corticotropin-releasing hormone levels. RESULTS: Rats exposed to a 4-week unavoidable stress showed escape deficit and their basal plasma corticosterone levels were higher than those of control animals. Moreover, they had decreased response to dexamethasone administration, adrenal hypertrophy, and decreased GR expression in the hippocampus, hypothalamus, medial prefrontal cortex and pituitary. No significant modifications in CRHR1 expression were observed in the pituitary nor in different discrete brain areas. CRH levels in the hypothalamus and the plasma corticosterone response to CRH administration were found to be higher in stressed rats than in controls. Imipramine treatment offset all the behavioral and neurochemical stress-induced modifications. In conclusion, the present results strengthen the assumption that the escape/avoidance behavioral deficit induced by inescapable stress exposure is accompanied by steadily increased HPA activity, and that imipramine effect is strongly related to a normalization of HPA axis activity.     

Appraisal dimensions of emotions: an empirical integration of the previous findings

Appraisal theories of emotions assume that the emotions are elicited by the appraisals of events or circumstances along with the several dimensions. However, there are some inconsistencies among the dimensions proposed by various appraisal theories. The purpose of this study was to integrate the appraisal dimensions that were proposed by Scherer, Roseman, and Smith & Ellsworth's theories by empirically investigating the appraisals associated with each emotion. Three hundred seventy-six Japanese participants recalled a past experience associated with one of 13 emotions, and rated the nature of the emotional event along the appraisal dimensions proposed by them. A factor analysis identified eight factors: pleasantness, self/other control, certainty, anticipated effort and attention, novelty, human/situation control, motivational state, and coping potentials. These dimensions were consistently proposed by the appraisal theorists. Moreover the associations between each emotion and its appraisal profiles were mostly consistent with the previous theories except for a few dimensions. Discussion argued that the appraisal dimensions identified in this study adequately capture the important features of major emotions.     

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。     

Deregulation of hypothalamic-pituitary-adrenal axis functions in an Alzheimer's disease rat model

Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β_25–35 peptide (Aβ_25–35) in rat, a validated acute model of AD. Aβ_25–35 induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ_25–35 induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ_25–35, which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity.     

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.     

Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological,physiological, and pharmacological stimulation

OBJECTIVES: Subtle alterations of the hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome (CFS) have been proposed as a shared pathway linking numerous etiological and perpetuating processes with symptoms and observed physiological abnormalities. Because the HPA axis is involved in the adaptive responses to stress and CFS patients experience a worsening of symptoms after physical and psychological stress, we tested HPA axis functioning with three centrally acting stress tests. METHODS: We used two procedures mimicking real-life stressors and compared them with a standardized pharmacological neuroendocrine challenge test. CFS patients were compared with healthy control subjects regarding their cardiovascular and endocrine reactivity in a psychosocial stress test and a standardized exercise test, and their endocrine response in the insulin tolerance test (ITT). RESULTS: Controlling for possible confounding variables, we found significantly lower ACTH response levels in the psychosocial stress test and the exercise test, and significantly lower ACTH responses in the ITT, with no differences in plasma total cortisol responses. Also, salivary-free cortisol responses did not differ between the groups in the psychosocial stress test and the exercise test but were significantly higher for the CFS patients in the ITT. In all tests CFS patients had significantly reduced baseline ACTH levels. CONCLUSIONS: These results suggest that CFS patients are capable of mounting a sufficient cortisol response under different types of stress but that on a central level subtle dysregulations of the HPA axis exist.     

Cortisol responses to emotional stress in men: association with a functional polymorphism in the 5HTR2C gene

The serotonin 5HTR2C receptor has been shown to mediate HPA axis activation during stress. We hypothesized that a functional polymorphism (rs6318) of the 5HTR2C gene would be associated with HPA axis response to a laboratory stress protocol. The present sample consisted of 41 men (22 African Americans, 19 Caucasians). We found that at rest men with the more active rs6318 Ser23 C allele had similar cortisol values compared to those with the less active Cys23 G allele. During laboratory stress, however, men with the Ser23 C allele exhibited the predicted significantly higher cortisol levels (p < 0.001), as well as larger increases in anger (p = 0.08) and depressive mood (p = 0.006) ratings, compared to the Cys23 G carriers. The increase in cortisol was significantly related to the increases in ratings of anger and depression assessed before and after the emotion induction, and these correlations became nonsignificant when rs6318 genotype was covaried. We conclude that genetic variation in 5HTR2C may be associated with HPA axis activation and stimulated by emotional stress, and also with both psychological and physiological endophenotypes that increase the risk of cardiovascular disease and type-2 diabetes.     

Emotion regulation in emerging adult couples: temperament, attachment, and HPA response to conflict

Difficulty managing the stress of conflict in close relationships can lead to mental and physical health problems, possibly through dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine stress response system. Temperament, an individual characteristic, and attachment, a dyadic characteristic, have both been implicated in emotion regulation processes and physiological reactivity, yet there is no clear consensus on how the two work together to influence the stress response, especially after childhood. The present study investigated the ways in which temperament and attachment together predict HPA response in emerging adult couples. Analyses using multilevel modeling (HLM) found that partners' dyadic fit on attachment avoidance impacted females' cortisol response patterns, and attachment avoidance further moderated the effect of males' emotionality on both their own and their partners' cortisol. Results are discussed in terms of emotional coregulation processes in romantic attachment.     

Behavior and metabolic disease

The link between behavioral factors and disease is not well-defined. Although connections between a fight-flight reaction to environmental stress and hypertension have been much discussed, a potential disease association to a defeat-type of reaction has been much less considered. This is characterized by an elevated activity of the hypothalamo-pituitary-adrenal (HPA) axis, which is difficult to measure over a sufficiently long period of time. There is now considerable evidence that the characteristic peripheral endocrine abnormalities following a chronic HPA axis activation is directing storage fat to central, visceral adipose tissue depots. This evidence come from detailed molecular and cellular studies, clinical observation, and intervention trials, as well as from statistical associations between visceral fat accumulation and HPA axis activation in a number of conditions. Central fat accumulation measured conveniently as the waist/hip circumference ratio (WHR), is therefore probably a surrogate measurement for a chronic or repeated activation of the HPA axis. The WHR consequently provides a possibility to examine connections between environmental factors resulting in a hyperactive HPA axis, which is a consequence of a defeat-type of reaction to perceived stress. Such statistical associations have been examined in several population samples. The WHR has been found to be linked to a number of psychosocial and socioeconomic handicaps among both men and women, as well as to traits of psychiatric disease and use of alcohol and tobacco. Measurements of moderate obesity without WHR elevation often show reverse relations. It is suggested that measurements of central fat distribution such as the WHR may be used as a surrogate for chronic or repeated HPA axis activation, a consequence of a defeat-type of reaction to perceived environmental stress. This may provide a novel, convenient method to trace adverse bodily consequences of environmental stress leading to disease. This is also suggested by the fact that the WHR is now an established, unusually powerful risk factor for several prevalent diseases, which were previously suggested to have links to psychosocial and socioeconomic handicaps.     

Anterior EEG asymmetries and opponent process theory.

The opponent process theory of emotion [Solomon, R.L., and Corbit, J.D. (1974). An opponent-process theory of motivation: I. Temporal dynamics of affect. Psychological Review, 81, 119-143.] predicts a temporary reversal of emotional valence during the recovery from emotional stimulation. We hypothesized that this affective contrast would be apparent in asymmetrical activity patterns in the frontal lobes, and would be more apparent for left frontally active individuals. The present study tested this prediction by examining EEG asymmetries during and after blocked presentations of aversive pictures selected from the International Affective Picture System (IAPS). 12 neutral images, 12 aversive images, and 24 neutral images were presented in blocks. Participants who were right frontally active at baseline did not show changes in EEG asymmetry while viewing aversive slides or after cessation. Participants left frontally active at baseline, however, exhibited greater relative left frontal activity after aversive stimulation than before stimulation. Asymmetrical activity patterns in the frontal lobes may relate to affect regulatory processes, including contrasting opponent after-reactions to aversive stimuli.     

Limbic and HPA axis function in an animal model of chronic neuropathic pain

Chronic pain can be considered a form of chronic stress, and chronic pain patients often have disturbances of the hypothalamic-pituitary-adrenal (HPA) axis, including abnormal cortisol levels. In addition, chronic pain patients have an increased incidence of depression and anxiety, stress-related disorders that are frequently accompanied by disturbances in the limbic system (e.g. hippocampus and amygdala) and the HPA axis. Despite the fact that the literature supports a strong link between chronic pain, stress disorders, and limbic dysfunction, the mechanisms underlying the effects of chronic pain on the HPA axis and limbic system are not understood. The current study employs a rodent neuropathic pain model (chronic constriction injury (CCI) of the sciatic nerve) to assess the long-term impact of chronic pain on the HPA axis and limbic system. Adult male rats received CCI or sham surgery; nociceptive behavioral testing confirmed CCI-induced neuropathic pain. Tests of HPA axis function at 13-23 days postsurgery demonstrated that CCI did not affect indices of basal or restraint stress-induced HPA axis activity. CCI increased the expression of corticotrophin releasing hormone mRNA in the central amygdala, and not the paraventricular nucleus of the hypothalamus or the bed nucleus of the stria terminalis. Moreover, glucocorticoid receptor mRNA expression in CCI rats was increased in the medial and central amygdala, unaffected in the paraventricular nucleus, and decreased in the hippocampus. These results suggest that increased nociceptive sensitivity during chronic pain is associated with alterations in the limbic system, but is dissociated from HPA axis activation.     

Effects of proadrenomedullin N-terminal 20 peptide on the rat pituitary-adrenocortical axis under basal and stressful conditions

Proadrenomedullin N-terminal 20 peptide (PAMP) derives, along with adrenomedullin (AM), from prepro-AM. AM has been reported to modulate the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and this study aimed at ascertaining whether PAMP exerts similar effects. PAMP was subcutaneously administered to non-stressed and stressed rats, and the plasma concentrations of ACTH and corticosterone were measured by radioimmune assay. In non-stressed rats, PAMP raised ACTH and corticosterone blood levels at 60 min, and ACTH plasma concentration at 120 min. Ether and cold stresses increased the plasma levels of both ACTH and corticosterone, and PAMP dampened HPA axis response to cold stress, without affecting that to ether stress. The conclusion is drawn that PAMP i) stimulates rat HPA axis, through a mechanism similar to that of ether stress; and ii) interferes with the neural pathways involved in the cold stress-induced activation of HPA axis.     

杏仁核与创伤后应激障碍发病机制的相关性

创伤后应激障碍(PTSD)是指由于异常威胁性或灾难性心理创伤导致延迟出现和长期持续的精神障碍。杏仁核是大脑中的"恐惧中枢",与创伤性记忆和应激时HPA轴的激活联系密切。PTSD患者有强烈的恐惧和惊吓反应,血中糖皮质激素浓度反常低下,下丘脑-垂体-肾上腺轴(HPA)轴调节紊乱。杏仁核可通过糖皮质激素受体(GR)和盐皮质激素受体(MR)调节激活HPA轴,增加糖皮质激素的释放。PTSD导致杏仁核神经元细胞凋亡,凋亡相关基因Bax和Bcl-2比值增大时,神经细胞出现凋亡。PTSD引发杏仁核神经元长时程增强(LTP),杏仁核是恐惧形成和表达的关键中枢。在恐惧条件反射的形成过程中,杏仁核发生LTP,表明LTP是反应PTSD发生机制的重要指标。PTSD引致乙酰胆碱酯酶(AChE)活性降低,乙酰胆碱增多,恐惧增强;PTSD导致杏仁核神经元MR、GR及MR/GR发生改变,激活HPA轴,导致HPA轴调节紊乱。     

Developmental psychopathology and neurobiology of aggression

The aim of this paper is to clarify how neural mechanisms at the molecular level, specifically the serotonergic (5-HT) system and the hypothalamic-pituitary-adrenal axis system (HPA) in conjunction with early life stress may contribute to the emergence of aggression, self-directed and otherwise, in borderline personality disorder (BPD). Chronic dysregulation of these biological systems, which function to regulate stress and emotion, may potentiate the development of impulsive aggression in borderline personality conditions. Our central premise in this paper is that brain development, stress regulation, and early pathonomic experience are interactive and cumulative in their mutual influence on the development of impulsive aggression in BPD. We review the parameters of impulsive aggression in BPD, followed by a discussion of the neurobiological and neuroendocrine correlates of impulsive aggression with and without BPD. We then focus on the developmental continuities in BPD with attention to brain maturation of 5-HT and HPA axis function during the life span and the influence of early adverse experiences on these systems. Finally, we comment on the data of the relative stability of aggression in BPD, adolescence as a developmental stage of potential vulnerability, and the course of aggressive behavior during the life span.     

Relationships between muscle mitochondrial metabolism and stress-induced corticosterone variations in rats

In order to determine the effect of chronic and acute stress on muscle mitochondrial metabolism, two strains of rats were selected on the basis of their different hypothalamo-pituitary-adrenal (HPA) axis responses to different stressors [Spontaneous Hypertensive Rats (SHR) and Lewis rats]. For 8 weeks animals were stressed by daily exposure to either a novel environment (SHR: n=16, Lewis: n=16) or forced exercise (SHR: n=16, Lewis: n=16). An unstressed group was left undisturbed (SHR: n=5, Lewis: n=5). Half of the stressed animals (n=32) were submitted to an acute stress (1-h immobilization). The mitochondrial responses of plantaris muscle [cytochrome-c-oxidase (COX), citrate synthase and succinate dehydrogenase activities, the latter two being measured as indices of functional mitochondrial amount] in the presence of different physiological plasma corticosterone (CORT) concentrations were analyzed. The novel environment and forced exercise stress induced different levels of plasma CORT which were negatively correlated with the amount of functional mitochondria in the plantaris muscle. Therefore, a chronic intermittent stress is able to induce an increase in plasma CORT which may be related to deleterious changes in muscle mitochondrial metabolism. Lastly, the acute stress was not associated with a decrease in functional mitochondria but with an increase in COX activity. This suggests that the relationship between CORT and muscle mitochondrial metabolism depends both on the level and duration of endogenous glucocorticoids exposure.     

Heterogeneity of neuroendocrine stress responses in aging rat strains

Hyperactivity of the hypothalamo-pituitary-adrenocortical (HPA) axis is linked with age-related decrements in cognition and neuronal survival. However, the nature and extent of age-related HPA axis deficits vary considerably across and indeed, within strains. The current study was designed to assess variance in HPA axis function using two rodent models commonly used in aging studies: Fischer 344 (F344) and F344/Brown-Norway F1 hybrid rats (F344/BN). We examined both basal and stress-induced ACTH and corticosterone (CORT) release in two stress contexts thought to differ in intensity: novel environment (‘mild’) and restraint (‘intense’). Variability of the data was tested with a modification of the Brown-Forsythe test of homoscedasticity. The results indicated that F344 rats exhibit greater peak HPA responses. Furthermore, in most cases variability was increased in aged rats relative to young and middle-aged rats of the same strain, indicative of the emergence of individual differences in stress responsivity amongst older rats. The results suggest that these older rat strains may be useful models to further assess individual differences in neuroendocrine aging.