Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS. Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.     

Model-Based Therapeutic Correction of Hypothalamic-Pituitary-Adrenal Axis Dysfunction

The hypothalamic-pituitary-adrenal (HPA) axis is a major system maintaining body homeostasis by regulating the neuroendocrine and sympathetic nervous systems as well modulating immune function. Recent work has shown that the complex dynamics of this system accommodate several stable steady states, one of which corresponds to the hypocortisol state observed in patients with chronic fatigue syndrome (CFS). At present these dynamics are not formally considered in the development of treatment strategies. Here we use model-based predictive control (MPC) methodology to estimate robust treatment courses for displacing the HPA axis from an abnormal hypocortisol steady state back to a healthy cortisol level. This approach was applied to a recent model of HPA axis dynamics incorporating glucocorticoid receptor kinetics. A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels. Suppression of biologically available cortisol may be achieved through the use of binding proteins such as CBG and certain metabolizing enzymes, thus offering possible avenues for deployment in a clinical setting. Treatment strategies can therefore be designed that maximally exploit system dynamics to provide a robust response to treatment and ensure a positive outcome over a wide range of conditions. Perhaps most importantly, a treatment course involving further reduction in cortisol, even transient, is quite counterintuitive and challenges the conventional strategy of supplementing cortisol levels, an approach based on steady-state reasoning.     

Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity. In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS. We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory). Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS. These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5' region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.     

Detrimental effects of chronic hypothalamic—pituitary—adrenal axis activation

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated.     

Interleukin-10 Regulated Gene Expression in Cells of Hypothalamic-Pituitary-Adrenal Axis Origin

1. Aim: The hypothalamic-pituitary-adrenal (HPA) axis is a mediator for interactions between the immune and neuroendocrine systems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been shown to activate the HPA axis. Recently, interleukin-10, an important anti-inflammatory cytokine in the immune system, has been shown to be expressed in the central nervous system and neuroendocrine system. Little is known, however, about IL-10’s functions in the HPA axis. 2. Methods: The Affymetrix DNA microarray (mouse genome U74Av2 Probe Array) was conducted to determine the gene expression profile regulated by IL-10 in cells of HPA axis origin. 3. Results: In this study, we analyzed gene expression regulated by IL-10 in cells derived from the HPA axis. The results showed that quorums of genes are modulated by IL-10 in these neuroendocrine cells. 4. Conclusions: These findings will provide a valuable repository to aid in understanding IL-10’s functions in the HPA axis at the molecular level.     

The immune system as a regulator of thyroid hormone activity

It has been known for decades that the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In contrast, far less is known about the extent to which the immune system collaborates in the regulation of endocrine activity. This is particularly true for immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis. Although thyroid-stimulating hormone (TSH) can be produced by many types of extra-pituitary cells--including T cells, B cells, splenic dendritic cells, bone marrow hematopoietic cells, intestinal epithelial cells, and lymphocytes--the functional significance of those TSH pathways remains elusive and historically has been largely ignored from a research perspective. There is now, however, evidence linking cells of the immune system to the regulation of thyroid hormone activity in normal physiological conditions as well as during times of immunological stress. Although the mechanisms behind this are poorly understood, they appear to reflect a process of local intrathyroidal synthesis of TSH mediated by a population of bone marrow cells that traffic to the thyroid. This hitherto undescribed cell population has the potential to microregulate thyroid hormone secretion leading to critical alterations in metabolic activity independent of pituitary TSH output, and it has expansive implications for understanding mechanisms by which the immune system may act to modulate neuroendocrine function during times of host stress. In this article, the basic underpinnings of the hematopoietic-thyroid connection are described, and a model is presented in which the immune system participates in the regulation of thyroid hormone activity during acute infection.     

冷刺激诱导的弱精子症大鼠模型肾上腺轴与甲状腺轴功能改变的研究

目的:研究冷刺激诱导建立的弱精子症模型大鼠HPA轴与HPT轴功能改变,探讨其生殖生物学意义。方法:取28只SPF级性成熟雄性SD大鼠随机分为正常对照组(N组,12只)与冷刺激组(C组,16只)。造模结束前对大鼠一般情况包括精神状态、体重、核心体温、尿量等进行检测。23周后通过精子功能的评定筛选弱精子症大鼠并建立弱精子症组(CA组),同时取外周血清、HPA轴、HPT轴相关组织;ELISA法和放射免疫法测定各组大鼠外周血清HPA、HPT轴相关激素水平,并在光镜下观察HPA轴和HPT轴相关组织形态学改变。结果:与N组相比,CA组大鼠反应迟钝,活动能力降低,夹尾试验评分显著降低,核心体温及尿量升高,差异显著(P0.05)。血清激素结果表现为CA组EPI显著升高,T3/T4比值亦显著升高,差异均具有统计学意义(P0.05)。光镜下可见N组各组织形态正常,与N组相比,CA组下丘脑室旁核神经细胞增生,排列紊乱;垂体细胞水肿,血窦不明显,嗜酸性细胞增多;肾上腺以皮、髓质水肿改变为主;甲状腺滤泡萎缩,上皮细胞增生。结论:冷刺激诱导建立的弱精子症大鼠模型可发生HPA轴功能改变,呈现慢性应激反应现象,提示,HPA轴功能改变参与该模型弱精子症的的发生发展过程。     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

Elevated Hair Cortisol Levels among Heroin Addicts on Current Methadone Maintenance Compared to Controls

Whether methadone maintenance treatment (MMT) can improve the basal function of the hypothalamic–pituitary–adrenal (HPA) axis, which is suppressed by long-term heroin consumption, is a matter of debate. The stress state and depression and anxiety symptoms may affect the basal activity of the HPA axis in MMT patients. However, the effect of psychological factors on HPA activity was not simultaneously controlled in previous studies. This study investigated differences in HPA basal activity between MMT patients and controls using psychological variables as covariates. The participants included 52 MMT patients and 41 age-matched, non-heroin-dependent controls. Psychological states were self-reported with the Perceived Stress Scale, Self-Rating Depression Scale and Self-Rating Anxiety Scale. The hair cortisol level was adopted as a biomarker of HPA basal activity and was determined with liquid chromatography tandem mass spectrometry. The results revealed that MMT patients had significantly higher hair cortisol levels than the controls (p<0.05), but the difference was not significant (p>0.05) when the perceived stress, depression and anxiety scores were used as covariates. We concluded that patients with long-term MMT showed higher basal activity of the HPA axis. The high chronic stress state and increase in depression and anxiety symptoms may mask the suppression effect of methadone on the HPA activity.     

Chronic Stress Suppresses the Expression of Cutaneous Hypothalamic–Pituitary–Adrenocortical Axis Elements and Melanogenesis

Chronic stress can affect skin function, and some skin diseases might be triggered or aggravated by stress. Stress can activate the central hypothalamic–pituitary–adrenocortical (HPA) axis, which causes glucocorticoid levels to increase. The skin has HPA axis elements that react to environmental stressors to regulate skin functions, such as melanogenesis. This study explores the mechanism whereby chronic stress affects skin pigmentation, focusing on the HPA axis, and investigates the role of glucocorticoids in this pathway. We exposed C57BL/6 male mice to two types of chronic stress, chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Mice subjected to either stress condition showed reduced melanogenesis. Interestingly, CRS and CUMS triggered reductions in the mRNA expression levels of key factors involved in the HPA axis in the skin. In mice administered corticosterone, decreased melanin synthesis and reduced expression of HPA axis elements were observed. The reduced expression of HPA axis elements and melanogenesis in the skin of stressed mice were reversed by RU486 (a glucocorticoid receptor antagonist) treatment. Glucocorticoids had no significant inhibitory effect on melanogenesis in vitro. These results suggest that, high levels of serum corticosterone induced by chronic stress can reduce the expression of elements of the skin HPA axis by glucocorticoid-dependent negative feedback. These activities can eventually result in decreased skin pigmentation. Our findings raise the possibility that chronic stress could be a risk factor for depigmentation by disrupting the cutaneous HPA axis and should prompt dermatologists to exercise more caution when using glucocorticoids for treatment.     

Direct and dam-mediated effects of prenatal dexamethasone on emotionality, cognition and HPA axis in adult Wistar rats

Prenatal stress can affect foetal neurodevelopment and result in increased risk of depression in adulthood. It promotes increased maternal hypothalamo–pituitary–adrenal gland (HPA) secretion of glucocorticoid (GC), leading to increased foetal and maternal GC receptor activity. Prenatal GC receptor activity is also increased during prenatal treatment with dexamethasone (DEX), which is commonly prescribed as a prophylactic treatment of preterm delivery associated morbid symptoms. Here, we exposed pregnant Wistar rats to 0.1 mg/kg/d DEX during the last week of pregnancy and performed cross-fostering at birth. In the adult offspring we then studied the effects of prenatal DEX exposure per se and the effects of rearing by a dam exposed to prenatal DEX. Offspring were assessed in the following paradigms testing biobehavioural processes that are altered in depression: progressive ratio schedule of reinforcement (anhedonia), Porsolt forced swim test (behavioural despair), US pre-exposure active avoidance (learned helplessness), Morris water maze (spatial memory) and HPA axis activity (altered HPA function). Responsiveness to a physical stressor in terms of HPA activity was increased in male offspring exposed prenatally to DEX. Despite this increased HPA axis reactivity, we observed no alteration of the assessed behaviours in offspring exposed prenatally to DEX. We observed impairment in spatial memory in offspring reared by DEX exposed dams, independently of prenatal treatment. This study does not support the hypothesis that prenatal DEX exposure leads to depression-like symptoms in rats, despite the observed sex-specific programming effect on HPA axis. It does however emphasise the importance of rearing environment on adult cognitive performances.     

Functional Programming of the Autonomic Nervous System by Early Life Immune Exposure: Implications for Anxiety

Neonatal exposure of rodents to an immune challenge alters a variety of behavioural and physiological parameters in adulthood. In particular, neonatal lipopolysaccharide (LPS; 0.05 mg/kg, i.p.) exposure produces robust increases in anxiety-like behaviour, accompanied by persistent changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. Altered autonomic nervous system (ANS) activity is an important physiological contributor to the generation of anxiety. Here we examined the long term effects of neonatal LPS exposure on ANS function and the associated changes in neuroendocrine and behavioural indices. ANS function in Wistar rats, neonatally treated with LPS, was assessed via analysis of tyrosine hydroxylase (TH) in the adrenal glands on postnatal days (PNDs) 50 and 85, and via plethysmographic assessment of adult respiratory rate in response to mild stress (acoustic and light stimuli). Expression of genes implicated in regulation of autonomic and endocrine activity in the relevant brain areas was also examined. Neonatal LPS exposure produced an increase in TH phosphorylation and activity at both PNDs 50 and 85. In adulthood, LPS-treated rats responded with increased respiratory rates to the lower intensities of stimuli, indicative of increased autonomic arousal. These changes were associated with increases in anxiety-like behaviours and HPA axis activity, alongside altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus. The current findings suggest that in addition to the commonly reported alterations in HPA axis functioning, neonatal LPS challenge is associated with a persistent change in ANS activity, associated with, and potentially contributing to, the anxiety-like phenotype. The findings of this study reflect the importance of changes in the perinatal microbial environment on the ontogeny of physiological processes.     

The Different Roles of Glucocorticoids in the Hippocampus and Hypothalamus in Chronic Stress-Induced HPA Axis Hyperactivity

Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can''t induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.     

Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation. In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r² = 0.49, p = 0.001), general fatigue (r² = 0.34, p = 0.01) and reduced activity (r² = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.     

Plasticity in the adrenocortical response of a free-living vertebrate: the role of pre- and post-natal developmental stress

Optimal functioning of the hypothalamo–pituitary–adrenal (HPA) axis is paramount to maximizing fitness in vertebrates. Research in laboratory mammals has suggested that maternally-induced stress can cause significant variation in the responsiveness of an offspring's HPA axis involving both pre- and post-natal developmental mechanisms. However, very little is known regarding effects of maternal stress on the variability of offspring adrenocortical functioning in free-living vertebrates. Here we use an experimental approach that independently lowers the quality of both the pre- and post-natal developmental environment to examine programming and plasticity in the responsiveness of the HPA axis in fledglings of a free-living passerine, the European starling (Sturnus vulgaris). We found that mimicking a hormonal signal of poor maternal condition via an experimental pre-natal increase in yolk corticosterone decreased the subsequent responsiveness of the HPA axis in fledglings. Conversely, decreasing the quality of the post-natal developmental environment (by decreasing maternal provisioning capability via a maternal feather-clipping manipulation) increased subsequent responsiveness of the HPA axis in fledglings, apparently through direct effects on nestling body condition. The plasticity of these responses was sex-specific with smaller female offspring showing the largest increase in HPA reactivity. We suggest that pre-natal, corticosterone-induced, plasticity in the HPA axis may be a ‘predictive adaptive response’ (PAR): a form of adaptive developmental plasticity where the advantage of the induced phenotype is manifested in a future life-history stage. Further, we introduce a new term to define the condition-driven post-natal plasticity of the HPA axis to an unpredictable post-natal environment, namely a ‘reactive adaptive response’ (RAR). This study confirms that the quality of both the pre- and post-natal developmental environment can be a significant source of variation in the responsiveness of the HPA axis, and provides a frame-work for examining ecologically-relevant sources of stress-induced programming and plasticity in this endocrine system in a free-living vertebrate, respectively.     

The adrenocortical response of tufted puffin chicks to nutritional deficits

In several seabirds, nutritional state of a nest-bound chick is negatively correlated with the activity of its hypothalamus–pituitary–adrenal (HPA) axis. Increased corticosterone (cort) secretion has been shown to facilitate changes in behavior that allow hungry chicks to obtain more food from parents. However, if parents are not willing/able to buffer their young from temporary food shortages, increased cort secretion could be detrimental to undernourished chicks. In a system where parents are insensitive to chick demands, low benefits and high costs of activation of the HPA-axis in hungry chicks should lead to a disassociation of the nutritional state of the young and the activity of its HPA-axis. We tested this novel hypothesis for the tufted puffin (Fratercula cirrhata), a seabird with intermittent provisioning of a nest-bound semi-precocial chick. We examined the HPA-axis activity of captive chicks exposed to the following: (1) a short-term (24 h) food deprivation; and (2) an array of prolonged (3 weeks) restrictions in feeding regimens. We found that in response to a short-term food deprivation chicks decreased baseline levels of cort and thyroid hormones. In response to prolonged restrictions, food-limited chicks exhibited signs of nutritional deficit: they had lower body mass, endogenous lipid reserves, and thyroid hormone titers compared to chicks fed ad libitum. However, baseline and maximum acute stress-induced levels of cort were also lower in food-restricted chicks compared to those of chicks fed ad libitum. These results support a major prediction of the study hypothesis that puffin chicks suppress HPA-axis activity in response to short- and long-term nutritional deficits. This physiological adaptation may allow a chick to extend its development in the nest, while eluding detrimental effects of chronic cort elevation.     

Antisense oligodeoxynucleotide effects on the hypothalamic-neurohypophysial system and the hypothalamic-pituitary-adrenal axis

The possibility of sequence-dependent, transient, and local inhibition of neuropeptide or neuropeptide receptor expression within the brain makes antisense targeting an attractive approach for those interested in the involvement of brain neuropeptide systems in behavioral and neuroendocrine regulation. Here, I describe our attempts to manipulate the synthetic activity of peptidergic systems of the hypothalamic-neurohypophysial system, i.e. , oxytocin and vasopressin, and the hypothalamic-pituitary-adrenal (HPA) axis by antisense oligodeoxynucleotides. Detailed experimental protocols including different approaches for intracerebral antisense application in anesthetized or conscious rats are provided. As a consequence of local oxytocin or vasopressin antisense treatment within the hypothalamic supraoptic nucleus, various aspects of the neuronal activity are already altered after a few hours. Thus, we monitored electrophysiological parameters of oxytocinergic and vasopressinergic neurons, stimulus-induced expression of the Fos protein in oxytocin neurons, and stimulated release of oxytocin or vasopressin into blood as well as within the hypothalamus by dendrites and cell bodies as measured by simultaneous microdialysis in blood and brain, shortly after a single acute antisense infusion. We also employed chronic antisense infusion via osmotic minipumps or by repeated local infusion into the targeted brain region; for example, septal vasopressin receptor downregulation impairs the ability of male rats to discriminate between juvenile rats. Further, reduction of the amount of available CRH, vasopressin, and oxytocin within the hypothalamic paraventricular nuclei alters the neuroendocrine stress response of the HPA axis.     

LPS Exposure Increases Maternal Corticosterone Levels,Causes Placental Injury and Increases IL-1Β Levels in Adult Rat Offspring: Relevance to Autism

Maternal immune activation can induce neuropsychiatric disorders, such as autism and schizophrenia. Previous investigations by our group have shown that prenatal treatment of rats on gestation day 9.5 with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally), which mimics infections by gram-negative bacteria, induced autism-like behavior in male rats, including impaired communication and socialization and induced repetitive/restricted behavior. However, the behavior of female rats was unchanged. Little is known about how LPS-induced changes in the pregnant dam subsequently affect the developing fetus and the fetal immune system. The present study evaluated the hypothalamic-pituitary-adrenal (HPA) axis activity, the placental tissue and the reproductive performance of pregnant Wistar rats exposed to LPS. In the adult offspring, we evaluated the HPA axis and pro-inflammatory cytokine levels with or without a LPS challenge. LPS exposure increased maternal serum corticosterone levels, injured placental tissue and led to higher post-implantation loss, resulting in fewer live fetuses. The HPA axis was not affected in adult offspring. However, prenatal LPS exposure increased IL-1β serum levels, revealing that prenatal LPS exposure modified the immune response to a LPS challenge in adulthood. Increased IL-1β levels have been reported in several autistic patients. Together with our previous studies, our model induced autistic-like behavioral and immune disturbances in childhood and adulthood, indicating that it is a robust rat model of autism.