Hypothalamic Corticotropin-releasing Hormone Expression Research Articles

Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice

High-fat diet (HFD) consumption leads to obesity and a chronic state of low-grade inflammation, named metainflammation. Notably, metainflammation contributes to neuroinflammation due to the increased levels of circulating free fatty acids and cytokines. It indicates a strict interplay between peripheral and central counterparts in the pathogenic mechanisms of obesity-related mood disorders. In this context, the impairment of internal hypothalamic circuitry runs in tandem with the alteration of other brain areas associated with emotional processing (i.e., hippocampus and amygdala). Palmitoylethanolamide (PEA), an endogenous lipid mediator belonging to the N-acylethanolamines family, has been extensively studied for its pleiotropic effects both at central and peripheral level.Our study aimed to elucidate PEA capability in limiting obesity-induced anxiety-like behavior and neuroinflammation-related features in an experimental model of HFD-fed obese mice.PEA treatment promoted an improvement in anxiety-like behavior of obese mice and the systemic inflammation, reducing serum pro-inflammatory mediators (i.e., TNF-α, IL-1β, MCP-1, LPS). In the amygdala, PEA increased dopamine turnover, as well as GABA levels. PEA also counteracted the overactivation of HPA axis, reducing the expression of hypothalamic corticotropin-releasing hormone and its type 1 receptor. Moreover, PEA attenuated the immunoreactivity of Iba-1 and GFAP and reduced pro-inflammatory pathways and cytokine production in both the hypothalamus and hippocampus. This finding, together with the reduced transcription of mast cell markers (chymase 1 and tryptase β2) in the hippocampus, indicated the weakening of immune cell activation underlying the neuroprotective effect of PEA. Obesity-driven neuroinflammation was also associated with the disruption of blood–brain barrier (BBB) in the hippocampus. PEA limited the albumin extravasation and restored tight junction transcription modified by HFD. To gain mechanistic insight, we designed an in vitro model of metabolic injury using human neuroblastoma SH-SY5Y cells insulted by a mix of glucosamine and glucose. Here, PEA directly counteracted inflammation and mitochondrial dysfunction in a PPAR-α-dependent manner since the pharmacological blockade of the receptor reverted its effects.Our results strengthen the therapeutic potential of PEA in obesity-related neuropsychiatric comorbidities, controlling neuroinflammation, BBB disruption, and neurotransmitter imbalance involved in behavioral dysfunctions.

Early life stress induces a transient increase in hippocampal corticotropin-releasing hormone in rat neonates that precedes the effects on hypothalamic neuropeptides.

Early life stress (ELS) programs hypothalamus-pituitary-adrenal (HPA) axis activity and affects synaptic plasticity and cognitive performance in adults; however, the effects of ELS during the temporal window of vulnerability are poorly understood. This study aimed to thoroughly characterize the effects of ELS in the form of periodic maternal separation (MS180) during the time of exposure to stress. Hippocampal corticotropin-releasing hormone (CRH) gene expression and baseline HPA axis activity were analyzed at postnatal (P) days 6, 12, 15, and 21, and in adulthood (P75); these factors were correlated with plasticity markers and adult behavior. Our results indicate that MS180 induces an increase in hippocampal CRH expression at P9, P12, and P15, whereas an increase in hypothalamic CRH expression was observed from P12 to P21. Increased arginine-vasopressin expression and corticosterone levels were observed only at P21. Moreover, MS180 caused transient alterations in hypothalamic synaptophysin expression during early life. As adults, MS180 rats showed a passive coping strategy in the forced swimming test, cognitive impairments in the object location test, increased hypothalamic CRH expression, and decreased oxytocin (OXT) expression. Spearman's analysis indicated that cognitive impairments correlated with CRH and OXT expression. In conclusion, our data indicate that MS180 induces a transient increase in hippocampal CRH expression in neonates that precedes the effects on hypothalamic neuropeptides, confirming the role of increased CRH during the temporal window of vulnerability as a mediator of some of the detrimental effects of ELS on brain development and adult behavior.

Av-UCP single nucleotide polymorphism affects heat production during cold exposure in chicks.

Uncoupling protein one (UCP1) is involved in thermogenesis, especially in non-shivering heat production. In chickens, a single nucleotide polymorphism (SNP) of the av-UCP (avian UCP) gene has been reported to be associated with body weight gain and increased abdominal fat. The purpose of this study was to examine the relationship between the av-UCP gene SNP and heat production in chicks. C/C and T/T male chicks (Rhode Island Red) of av-UCP gene SNP (g. 1270, C>T) were exposed to a low temperature environment (16°C for 15min) and their physiological responses were compared. After cold exposure, mean rectal temperatures of C/C chicks were higher than those of T/T chicks. In pectoral muscle, genes expression of av-UCP and carnitine palmitoyltransferase-1 were higher in C/C chicks than T/T chicks. Hypothalamic expression levels of thyrotropin-releasing hormone and proopiomelanocortin genes were higher in C/C chicks than T/T chicks. Expression of hypothalamic corticotropin-releasing hormone, arginine vasotocin, brain-derived neurotrophic factor and neuropeptide Y genes did not differ between C/C and T/T chicks. In addition, plasma free fatty acid levels in C/C chicks were lower than those of T/T chicks. These results suggest that the av-UCP gene SNP affects non-shivering heat production via the hypothalamo-pituitary-thyroid axis and fatty acid metabolism in the chicken.

The Hypothalamic-Pituitary-Adrenal Axis and Serotonin Metabolism in Individual Brain Nuclei of Mice with Genetic Disruption of the NK1 Receptor Exposed to Acute Stress.

Mice lacking the substance P (SP) neurokinin-1 (NK1) receptor (NK1R-/-mice) were used to investigate whether SP affects serotonin (5-HT) function in the brain and to assess the effects of acute immobilisation stress on the hypothalamic-pituitary-adrenocortical (HPA) axis and 5-HT turnover in individual brain nuclei. Basal HPA activity and the expression of hypothalamic corticotropin-releasing hormone (CRH) in wild-type (WT)- and NK1R-/- mice were identical. Stress-induced increases in plasma ACTH concentration were considerably higher in NK1R-/- mice than in WT mice while corticosterone concentrations were equally elevated in both mouse lines. Acute stress did not alter the expression of CRH. In the dorsal raphe nucleus (DRN), basal 5-HT turnover was increased in NK1R-/- mice and a 15min stress further magnified 5-HT utilisation in this region. In the frontoparietal cortex, medial prefrontal cortex, central nucleus of amygdala, and the hippocampal CA1 region, stress increased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations to a similar extent in WT and NK1R-/- mice. 5-HT turnover in the hypothalamic paraventricular nucleus was not affected by stress, but stress induced similar increases in 5-HT and 5-HIAA in the ventromedial and dorsomedial hypothalamic nuclei in WT and NK1R-/- mice. Our findings indicate that NK1 receptor activation suppresses ACTH release during acute stress but does not exert sustained inhibition of the HPA axis. Genetic deletion of the NK1 receptor accelerates 5-HT turnover in DRN under basal and stress conditions. No differences between the responses of serotonergic system to acute stress in WT and NK1R-/- mice occur in forebrain nuclei linked to the regulation of anxiety and neuroendocrine stress responses.

Hierarchy in the home cage affects behaviour and gene expression in group-housed C57BL/6 male mice

Group-housed male mice exhibit aggressive behaviour towards their cage mates and form a social hierarchy. Here, we describe how social hierarchy in standard group-housed conditions affects behaviour and gene expression in male mice. Four male C57BL/6 mice were kept in each cage used in the study, and the social hierarchy was determined from observation of video recordings of aggressive behaviour. After formation of a social hierarchy, the behaviour and hippocampal gene expression were analysed in the mice. Higher anxiety- and depression-like behaviours and elevated gene expression of hypothalamic corticotropin-releasing hormone and hippocampal serotonin receptor subtypes were observed in subordinate mice compared with those of dominant mice. These differences were alleviated by orally administering fluoxetine, which is an antidepressant of the selective serotonin reuptake inhibitor class. We concluded that hierarchy in the home cage affects behaviour and gene expression in male mice, resulting in anxiety- and depression-like behaviours being regulated differently in dominant and subordinate mice.

Effect of dexamethasone on hypothalamic expression of appetite-related genes in chickens under different diet and feeding conditions.

BackgroundGlucocorticoids (GCs) are involved in the control of appetite in birds and mammals. The effect of GCs on feed intake in birds depends on their dietary energy level. But the regulation mechanism of GCs on appetite is still unclear in chickens facing to different energy level. An experiment was conducted to investigate the effect of dexamethasone (DEX) on hypothalamic expression of appetite-related peptides in chickens fed high/low fat diet and under fasting/feeding condition.ResultsAn interaction between DEX injection and dietary energy level was found on hypothalamic corticotropin-releasing hormone (CRH) gene expression in fasted chickens (P < 0.05). The chickens, given a DEX injection and a low fat diet treatment, had the highest CRH mRNA levels than any of the fasted chickens given treatments (P < 0.05). Under fasting conditions, the DEX treatment significantly increased hypothalamic neuropeptide Y (NPY) and GC receptors mRNA levels (P < 0.05). Under re-feeding conditions, DEX treatment significantly decreased hypothalamic expression levels of NPY and agouti-related peptide (AgRP) but significantly increased the level of hypothalamic CRH expression (P < 0.05).ConclusionA regulatory network formed by NPY, AgRP and CRH is associated with the appetite-control by GCs. The result suggests that the regulation of GCs on orexigenic neuropeptides expression is dependent at least partially on dietary energy level and feeding state.Electronic supplementary materialThe online version of this article (doi:10.1186/s40104-016-0084-x) contains supplementary material, which is available to authorized users.

Depression-like Behavior Induced by Nesfatin-1 in Rats: Involvement of Increased Immune Activation and Imbalance of Synaptic Vesicle Proteins.

Depression is a multicausal disorder and has been associated with metabolism regulation and immuno-inflammatory reaction. The anorectic molecule nesfatin-1 has recently been characterized as a potential mood regulator, but its precise effect on depression and the possible mechanisms remain unknown, especially when given peripherally. In the present study, nesfatin-1 was intraperitoneally injected to the rats and the depression-like behavior and activity of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated. The plasma concentrations of nesfatin-1, interleukin 6 (IL-6), and C-reactive protein (CRP); and the hypothalamic expression levels of nesfatin-1, synapsin I, and synaptotagmin I mRNA were evaluated in nesfatin-1 chronically treated rats. The results showed that both acute and chronic administration of nesfatin-1 increased immobility in the forced swimming test (FST), and resulted in the hyperactivity of HPA axis, as indicated by the increase of plasma corticosterone concentration and hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Moreover, after chronic nesfatin-1 administration, the rats exhibited decreased activity and exploratory behavior in the open field test (OFT) and increased mRNA expression of synapsin I and synaptotagmin I in the hypothalamus. Furthermore, chronic administration of nesfatin-1 elevated plasma concentrations of IL-6 and CRP, which were positively correlated with despair behavior, plasma corticosterone level, and the hypothalamic mRNA expression of synapsin I and synaptotagmin I. These results indicated that exogenous nesfatin-1 could induce the immune-inflammatory activation, which might be a central hug linking the depression-like behavior and the imbalanced mRNA expression of synaptic vesicle proteins in the hypothalamus.

Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.

Maternal flaxseed diet during lactation changes adrenal function in adult male rat offspring.

Flaxseed (Linum usitatissimum L.) has been a focus of interest in the field of functional foods because of its potential health benefits. However, we hypothesised that maternal flaxseed intake during lactation could induce several metabolic dysfunctions in adult offspring. In the present study, we aimed to characterise the adrenal function of adult offspring whose dams were supplemented with whole flaxseed during lactation. At birth, lactating Wistar rats were divided into two groups: rats from dams fed the flaxseed diet (FLAX) with 25% of flaxseed and controls dams. Pups received standard diet after weaning and male offspring were killed at age 180 days old to collect blood and tissues. We evaluated body weight and food intake during development, corticosteronaemia, adrenal catecholamine content, hepatic cholesterol, TAG and glycogen contents, and the protein expression of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and adrenaline β2 receptor at postnatal day 180 (PN180). After weaning, pups from the FLAX group had a higher body weight (+10 %) and food intake (+10%). At PN180, the FLAX offspring exhibited higher serum corticosterone (+48%) and lower adrenal catecholamine ( - 23%) contents, lower glycogen ( - 30%), higher cholesterol (4-fold increase) and TAG (3-fold-increase) contents in the liver, and higher 11β-HSD1 (+62%) protein expression. Although the protein expression of hypothalamic CRH was unaffected, the FLAX offspring had lower protein expression of pituitary ACTH ( - 34%). Therefore, induction of hypercorticosteronaemia by dietary flaxseed during lactation may be due to an increased hepatic activation of 11β-HSD1 and suppression of ACTH. The changes in the liver fat content of the FLAX group are suggestive of steatosis, in which hypercorticosteronaemia may play an important role. Thus, it is recommended that lactating women restrict the intake of flaxseed during lactation.

Acute, but not chronic, stress increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats

Nesfatin-1, a newly discovered satiety peptide, has recently been reported to be involved in the stress response. Stress-induced expression of nesfatin-1 has been reported and few studies focus on its expression in the hypothalamus, which is the center of the stress response. To test our hypothesis that peripheral and hypothalamic nesfatin-1 overexpression should play an important role in the stress response and the associated hyperactivity of hypothalamic–pituitary–adrenal (HPA) axis, acute stress (AS) was induced using water avoidance stress (WAS), and chronic unpredictable mild stress (CUMS) was also induced using 3 consecutive weeks of 7 different stressors. The behavior of CUMS rats was evaluated by an open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). The activity of the HPA axis was detected by measurement of the plasma corticosterone concentration and hypothalamic mRNA expression of corticotropin-releasing-hormone (CRH). The plasma concentration and hypothalamic mRNA expression of nesfatin-1 were measured with an enzyme-linked immunosorbent assay (ELISA) and real-time fluorescent quantitative PCR, respectively. The results showed that both AS and CUMS increased the plasma corticosterone concentration and hypothalamic CRH mRNA expression. Depression-like behavior was induced in CUMS rats, as indicated by a decreased movement distance, frequency of rearing and grooming in the OFT, and sucrose preference index and increased immobility in the FST. Moreover, the AS rats showed increased plasma concentration and hypothalamic mRNA expression of nesfatin-1, which were positively correlated with the plasma corticosterone concentration and hypothalamic CRH expression, respectively. These results indicated that acute stress, but not chronic stress, increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats.

Effects of energy restriction on activity of the hypothalamo-pituitary-adrenal axis in obese humans and rodents: implications for diet-induced changes in body composition.

Obesity treatments aim to maximize fat loss, particularly abdominal or visceral fat, without compromising lean or bone mass. However, the literature contains numerous examples of obesity treatments that - in addition to fat loss - result in loss of lean mass and/or bone mass. Because of the known effects of energy restriction to increase activity of the hypothalamo-pitutiary adrenal (HPA) axis in lean humans and animals, and because increases in circulating glucocorticoid levels could potentially contribute to adverse body compositional changes with obesity treatments, we conducted a systematic PubMed search to determine whether HPA axis activation also occurs in response to energy restriction in obese humans and animals. In most studies in obese humans, short-term severe energy restriction increased circulating cortisol levels, and this response was also seen in two longer-term human studies involving severe or moderate energy restriction. These findings parallel studies on short- or long-term energy restriction in obese rodents, with most studies showing increases in circulating corticosterone concentrations, and no change or actual increases in hypothalamic expression of corticotropin-releasing hormone, urocortin 3 or their receptors. However, a significant proportion of studies involving longer-term severe or moderate energy restriction in obese humans showed no change or decreases in HPA axis function. There was variability among human studies in the duration of energy restriction and timing of the HPA axis investigations (i.e., during energy restriction, or after a period of post-restriction weight maintenance). In order to unambiguously determine changes in HPA axis function with energy restriction in obese humans, it will be important to assess HPA axis function at multiple time points during energy restriction, given that obese individuals may spend many weeks or months in severe or moderate energy restriction in order to reduce excess weight, and given that increases in glucocorticoid function can have significant effects on body composition within weeks to months.

Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus

Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in the hypothalamus, CRH is constitutively expressed and this expression is further enhanced by stress; however, the underlying regulatory mechanisms are not fully understood. The regulatory region of the crh gene contains several elements, including the cyclic-AMP response element (CRE), and the role of the CRE interaction with the cyclic-AMP response element binding protein (CREB) in CRH expression has been a focus of intensive research. Notably, whereas thousands of genes contain a CRE, the functional regulation of gene expression by the CRE:CREB system is limited to ∼100 genes, and likely requires additional proteins. Here, we investigated the role of a member of the CREB complex, CREB binding protein (CBP), in basal and stress-induced CRH expression during development and in the adult. Using mice with a deficient CREB-binding site on CBP, we found that CBP:CREB interaction is necessary for normal basal CRH expression at the mRNA and protein level in the nine-day-old mouse, prior to onset of functional regulation of hypothalamic CRH expression by glucocorticoids. This interaction, which functions directly on crh or indirectly via regulation of other genes, was no longer required for maintenance of basal CRH expression levels in the adult. However, CBP:CREB binding contributed to stress-induced CRH expression in the adult, enabling rapid CRH synthesis in hypothalamus. CBP:CREB binding deficiency did not disrupt basal corticosterone plasma levels or acute stress-evoked corticosterone release. Because dysregulation of CRH expression occurs in stress-related disorders including depression, a full understanding of the complex regulation of this gene is important in both health and disease.

Altered colonic function and microbiota profile in a mouse model of chronic depression

Background Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms.Methods Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles.Key Results Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon.Conclusions & Inferences The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.

Developmental alterations in CNS stress-related gene expression following postnatal immune activation

Early-life adversity is associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and increased susceptibility to later-life psychopathology. Specifically, there is mounting evidence suggesting that the immune system plays an important role in central nervous system (CNS) development and in the programing of behavior. The current study investigated how early-life immune challenge affects the development of CNS stress neurocircuitry by examining the gene expression profile of corticotropin-releasing hormone (CRH), CRH receptors, and the major corticosteroid receptors within the limbic-hypothalamic circuit of the developing rodent brain. Mice were administered a 0.05mg/kg lipopolysaccharide (LPS) injection on postnatal day (P) 3 and 5 and gene expression was assessed using in situ hybridization from P14 to P28. Target genes investigated were CRH, CRH receptor-1 (CRHR1), CRH receptor-2, the mineralocorticoid receptor, and the glucocorticoid receptor (GR). Early LPS challenge resulted in a transient decrease in CRHR1 mRNA expression in the cornuammonis 1 (CA1) and CA3 regions of the hippocampus that were accompanied by increased hippocampal GR mRNA expression in the CA1 region between P14 and P21. This was followed by increased hypothalamic CRH expression in LPS-mice on P28. Our current findings suggest that early-life LPS challenge impacts the developmental trajectory of CNS stress neurocircuitry. These results lend insight into the molecular basis for the later development of stress-related behaviors as previously described in early immune challenge rodents.

Effect of Corticosterone on Hypothalamic Corticotropin-releasing Hormone Expression in Broiler Chicks (Gallus gallus domesticus) Fed a High Energy Diet

This paper reports the peripheral and central effect of corticosterone on feed intake and hypothalamic corticotropin- releasing hormone (CRH) gene expression in chicks fed a high energy diet. Three experiments were conducted: corticosterone was supplemented to the feed (30 mg/kg diet), injected subcutaneously (s.c., 4 mg/kg body weight) or intracerebroventricularly (i.c.v., 4 ng). The results showed that dietary corticosterone significantly increased feed intake. The s.c. corticosterone administration increased feed intake within 1 to 3 h and at 1 to 5 h after the injection. The i.c.v. corticosterone administration increased feed intake within 1 h after the injection, but not at 1 to 3 h. Dietary supplementation and s.c. injection of corticosterone decreased the CRH gene expression in the hypothalamus. Therefore, peripheral corticosterone exerted a decreased effect on hypothalamic CRH mRNA levels, and corticosterone had a stimulating effect on feed intake in broiler chicks fed a high energy diet. (Key Words : Broiler Chicks, Corticosterone, Corticotropin-releasing Hormone, Feed Intake)

Corticotropin-Releasing Hormone (CRH) Programs the Fetal and Maternal Brain.

Corticotropin-releasing hormone (CRH) is a 41-amino acid neuropeptide that is synthesized primarily in the paraventricular nucleus of the hypothalamus and has a major role in regulating pituitary-adrenal function and the physiological response to stress [1,2]. The hypothalamic-pituitary-adrenal (HPA) axis participates in a remarkable surveillance and response system which has evolved and is conserved, so that many species from the desert dwelling Western Spadefoot tadpole to the human fetus can detect threats to survival and adjust their developmental trajectory [3,4]. For instance, rapidly evaporating pools of desert water result in elevation of CRH in the pathway between the brain and the pituitary gland (median eminence) of the tadpole, initiating metamorphic climax to escape imminent peril [5,6]. If the CRH response is blocked during environmental desiccation, then the rate of development is arrested and the tadpole's survival is compromised. There are long-term consequences for the tadpole that survives this stressful challenge because its growth is stunted and it is at a disadvantage in competing with a normally developing toad foraging for food or reproducing. Normally, as described for the tadpole, stress activates the expression of hypothalamic CRH which stimulates the cascade of events preparing the organism for “fight or flight”. The maternal HPA system is altered dramatically during human pregnancy because the placenta expresses the genes for CRH. Placental CRH (pCRH) increases several hundred-fold as pregnancy advances and reaches levels in the maternal circulation at term observed only in the hypothalamic portal system during physiological stress [7]. In contrast to the inhibitory influence of maternal stress signals (e.g. cortisol) on expression of the CRH gene in the hypothalamus, maternal cortisol activates the promoter region in the placenta and stimulates its synthesis [8,9]. This positive feedback system contains both a signal to the fetus (elevated cortisol) that the host environment (the mother) is threatened [10], and a measurable response from the fetus (increased pCRH production). The rapid increase in pCRH that is stimulated by stress signals from the mother begins a cascade of events resulting in myometrial activation and in extreme cases, premature birth [11]. Human infants born early suffer a similar fate as the tadpole including a panoply of motor, sensory and neurological impairments that persist for a lifetime [12,13]. There are well-established neurological consequences associated with preterm birth, however it is the intrauterine conditions that determine the birth phenotype and alter the developmental trajectory. The fetus whether born early or at term, participates in its own development by incorporating messages about the nature of the maternal and intrauterine milieu and adapting its developmental program to prepare for postnatal survival. In addition to the growing acceptance that a significant proportion of variation in infant and adult health outcomes and disease risk is attributable to developmental processes during fetal life in response to a variety of environmental, social, psychological, physiological and genetic influences, there is newer information that the host, the mother, also is programmed by the processes specific and unique to pregnancy.

Hypothalamic CRH expression in fractalkine receptor (CX3CR1) deficient mouse

Event Abstract Back to Event Hypothalamic CRH expression in fractalkine receptor (CX3CR1) deficient mouse Andrea Molnár1* and Krisztina J. Kovacs1 1 Institute of Experimental Medicine, Hungary There is a bidirectional communication between immune system and neuroendocrine sytem, e.g. cytokines activate to hypothalamic-pituitary-adrenal axis. In the central nervous system (CNS), microglia act as immune competent cells. Fractalkine, secreted by neurons, affect microglial activation.Recently CX3CR1 deficient mice became available. In these animals, cx3cr1 gene was replaced by a GFP reporter gene. In both homozygote (CX3CR1GFP/GFP) and heterozygote (CX3CR1+/GFP) mice microglial cells can be revealed by GFP, but the CX3CR1GFP/GFP mice have complete absence of fractalkine receptor. The phenotype of CX3CR1+/GFP mice corresponds with wild type C57Bl6 mouse strain. To reveal the role of fractalkine receptor in mediation of immune signals to the hypothalamus, CX3CR1 trangenic animals were exposed to chronic variable stress paradigm and corticotropin-releasing hormone (CRH) expression has been evaluated.Under baseline conditions, in homozygote animals CRH mRNA levels are increased in the paraventricular nucleus (PVN), but sex difference in CRH expression remained. After chronic stress, in heterozygote males the CRF expression increased, while in the heterozygote females this increase is not significant. The increase is also not significant in the homozygote males. However, in the homozygote females the CRF expression are significantly decreased. This data suggests as role of microglial fractalkine receptor in regulation of hypothalamic stress related gene expression. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Homeostatic regulatory mechanisms Citation: Molnár A and Kovacs KJ (2009). Hypothalamic CRH expression in fractalkine receptor (CX3CR1) deficient mouse. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.115 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Mar 2009; Published Online: 04 Mar 2009. * Correspondence: Andrea Molnár, Institute of Experimental Medicine, Budapest, Hungary, molnara@koki.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Andrea Molnár Krisztina J Kovacs Google Andrea Molnár Krisztina J Kovacs Google Scholar Andrea Molnár Krisztina J Kovacs PubMed Andrea Molnár Krisztina J Kovacs Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

CRH mRNA expression in the hypothalamic paraventricular nucleus is inhibited despite the activation of the hypothalamo-pituitary-adrenal axis during starvation

Corticotropin-releasing hormone (CRH) is one of the anorexigenic neuropeptides, and indeed the expression of hypothalamic CRH is known to be inhibited by starvation. To clarify whether elevated plasma glucocorticoid during starvation is responsible for the CRH suppression, we examined the expression level of hypothalamic CRH mRNA after food deprivation in adrenalectomized, plasma corticosterone (B)-clamped animals. Male Wistar rats were divided into 2 groups: one group had adrenalectomy (ADX) and B pellet implantation (ADX + B, n = 42), and the other group had only sham operation (sham, n = 42). Rats were then treated with either ad libitum food supply or food deprivation for up to 96 h. The expression of CRH mRNA in the paraventricular nucleus (PVN) was estimated by in situ hybridization. After food deprivation, mean plasma B level was markedly elevated in sham group, but almost clamped in the ADX + B group. In this experimental condition, CRH mRNA in the PVN was significantly decreased in the sham group, whereas no change was obtained in the ADX + B group. Our data suggest the decrease in CRH mRNA seems to be related to the elevated glucocorticoid level during starvation. The status of hyperadrenocorticism without activation of CRH led us to speculate that adrenocortical function is predominant in the hypothalamic-pituitary-adrenal (HPA) axis during starvation.

Interleukin-6 and the Hypothalamic-Pituitary-Adrenal Activation in a Tumor Bearing Mouse

Tumor derived cytokines have been suggested to activate the hypothalamic-pituitary-adrenal (HPA) axis; that is, increase the hypothalamic releases of corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone. The authors previously reported that tumor mice bearing a human oral squamous cell carcinoma exhibit an anorectic phenotype with increased expression of CRH mRNA in their hypothalamic paraventricular nuclei. This study examined the plasma levels of tumor-derived cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in order to determine potential mediator(s) implicated in CRH expression in this tumor mouse model. Plasma corticosterone levels were assayed as well to confirm the HPA activation. In the results, plasma levels of IL-6, but not TNF-α, were increased significantly in the tumor mice compared with age-matching non-tumor controls. Plasma corticosterone levels were also increased in the tumor mice. These results together with the previous findings suggest IL-6 as a potential mediator in the control of hypothalamic CRH expression in the authors’ tumor mouse model.

Neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level are increased in the hypothalamus of mouse bearing a human oral squamous cell carcinoma

We examined gene expression of corticotropin-releasing hormone and neuropeptide Y level in the hypothalamic paraventricular nucleus of mouse bearing a human oral squamous cell carcinoma. A cell line derived from a human oral squamous cell carcinoma was inoculated into the lower dorsal area of nude mice. Body weight, tumor size and daily food intake were recorded every morning. Mice were sacrificed for corticotropin-releasing hormone mRNA in situ hybridization and neuropeptide Y immunohistochemistry, when the tumor ratio reached to 11-13% of real body weight. The results were compared with the age-matching non-tumor controls injected with saline instead of carcinoma cell. Body weight gain was significantly reduced in tumor bearing mice, however, no compensatory hyperphagia was found, i.e. daily food intake of the tumor mice did not differ from the non-tumor mice. Both neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level were significantly increased in the hypothalamic paraventricular nucleus of tumor mice. These results suggest that a human oral squamous cell carcinoma may induce anorexia, at least partly, via increasing the hypothalamic expression of corticotropin-releasing hormone in the tumor subjects. Additionally, neuropeptide Y-induced feeding appears to be inhibited in this tumor anorexia model, and this may correlate with increased expression of corticotropin-releasing hormone.