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Corticotropin-releasing hormone (CRH) cells are the dominant neuronal population responsive to the growth hormone (GH) in the paraventricular nucleus of the hypothalamus (PVH). However, the physiological importance of GH receptor (GHR) signaling in CRH neurons is currently unknown. Thus, the main objective of the present study was to investigate the consequences of GHR ablation in CRH-expressing cells of male and female mice. GHR ablation in CRH cells did not cause significant changes in body weight, body composition, food intake, substrate oxidation, locomotor activity, glucose tolerance, insulin sensitivity, counterregulatory response to 2-deoxy-D-glucose and ghrelin-induced food intake. However, reduced energy expenditure was observed in female mice carrying GHR ablation in CRH cells. The absence of GHR in CRH cells did not affect anxiety, circadian glucocorticoid levels or restraint-stress-induced corticosterone secretion and activation of PVH neurons in both male and female mice. In summary, GHR ablation, specifically in CRH-expressing neurons, does not lead to major alterations in metabolism, hypothalamic-pituitary-adrenal axis, acute stress response or anxiety in mice. Considering the previous studies showing that central GHR signaling regulates homeostasis in situations of metabolic stress, future studies are still necessary to identify the potential physiological importance of GH action on CRH neurons.
Preterm birth before 37th wk of gestation is called premature birth. Corticotropin-releasing hormone (CRH) and CRH-binding protein (BP) act on various maternal and fetal tissues during pregnancy, such as the myometrium, which regulates the transition from the dormant phase of the uterus to the active phase. Studies have shown that mir-200c and mir-181a interact with CRH and CRH-BP.
The expression of the corticotropin-releasing hormone (PmCRH) and the CRH-binding protein (PmCRHBP) mRNAs was studied by in situ hybridization in the brain of prolarvae, larvae, and adults of the sea lamprey Petromyzon marinus. We also generated an antibody against the PmCRH mature peptide to study the distribution of PmCRH-immunoreactive cells and fibers. PmCRH immunohistochemistry was combined with antityrosine hydroxylase immunohistochemistry, PmCRHBP in situ hybridization, or neurobiotin transport from the spinal cord. The most numerous PmCRH-expressing cells were observed in the magnocellular preoptic nucleus-paraventricular nucleus and in the superior and medial rhombencephalic reticular formation. PmCRH expression was more extended in adults than in larvae, and some cell populations were mainly (olfactory bulb) or only (striatum, ventral hypothalamus, prethalamus) observed in adults. The preopto-paraventricular fibers form conspicuous tracts coursing toward the neurohypophysis, but many immunoreactive fibers were also observed coursing in many other brain regions. Brain descending fibers in the spinal cord mainly come from cells located in the isthmus and in the medial rhombencephalic reticular nucleus. The distribution of PmCRHBP-expressing neurons was different from that of PmCRH cells, with cells mainly present in the septum, striatum, preoptic region, tuberal hypothalamus, pretectum, pineal complex, isthmus, reticular formation, and spinal cord. Again, expression in adults was more extended than in larvae. PmCRH- and PmCRHBP-expressing cells are different, excluding colocalization of these substances in the same neuron. Present findings reveal a complex CRH/CRHBP system in the brain of the oldest extant vertebrate group, the agnathans, which shows similarities but important divergences with that of mammals.
Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein-coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.
Angiogenesis is the formation of new blood vessels from existing ones and an underlying cause of numerous human diseases, including cancer and inflammation. A large body of evidence indicates that angiogenic inhibitors have therapeutic potential in the treatment of vascular diseases. However, detrimental side effects and low efficacy hinder their use in clinical practice. Members of the corticotropin-releasing hormone (CRH) family, which comprises CRH, urocortin I-III, and CRH receptors (CRHR) 1 and 2, are broadly expressed in the brain and peripheral tissues, including the intestine and cardiovascular system. The CRH family regulates stress-related responses through the hypothalamic-pituitary-adrenal axis. Therapeutic agents that target CRH family members offer a new approach to the treatment of various gastrointestinal disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and colorectal cancer. Since the discovery that CRHR 2 has anti-angiogenic activity during postnatal development in mice, studies have focused on the role of the CRH system in the modulation of blood vessel formation and cardiovascular function. This review will outline the basic biological functions of the CRH family members and the implications for the development of novel anti-angiogenic therapies.
The aim of this study was to determine whether corticotropin-releasing hormone (CRH) regulates human trophoblast cell growth. The results showed that exogenous CRH significantly stimulated human trophoblast proliferation in first-trimester primary cultures. In vivo, CRH was strongly immunolocalised to cytotrophoblastic cells in proliferative cell columns and in chorionic villi. We postulate that CRH may have an important role in early placental development and successful pregnancy.
Dissection of the neural circuits of the cerebral cortex is essential for studying mechanisms underlying brain function. Herein, combining a retrograde rabies tracing system with fluorescent micro-optical sectional tomography, we investigated long-range input neurons of corticotropin-releasing hormone containing neurons in the six main cortical areas, including the prefrontal, somatosensory, motor, auditory, and visual cortices. The whole brain distribution of input neurons showed similar patterns to input neurons distributed mainly in the adjacent cortical areas, thalamus, and basal forebrain. Reconstruction of continuous three-dimensional datasets showed the anterior and middle thalamus projected mainly to the rostral cortex whereas the posterior and lateral projected to the caudal cortex. In the basal forebrain, immunohistochemical staining showed these cortical areas received afferent information from cholinergic neurons in the substantia innominata and lateral globus pallidus, whereas cholinergic neurons in the diagonal band nucleus projected strongly to the prefrontal and visual cortex. Additionally, dense neurons in the zona incerta and ventral hippocampus were found to project to the prefrontal cortex. These results showed general patterns of cortical input circuits and unique connection patterns of each individual area, allowing for valuable comparisons among the organisation of different cortical areas and new insight into cortical functions.
A 47-yr-old woman with severe Cushing's syndrome had a bronchial carcinoid secreting ACTH and corticotropin-releasing hormone (CRH) and associated pituitary corticotroph hyperplasia. While the clinical picture was consistent with the ectopic ACTH syndrome, the biochemical pattern was that of pituitary ACTH-dependent hypercortisolism. Both plasma ACTH and CRH levels were high. However, while plasma ACTH increased during metyrapone administration and decreased during administration of high dose of dexamethasone, plasma CRH levels did not change, suggesting a direct pituitary response to these testing maneuvers. Immunoperoxidase staining of the tumor tissue confirmed the presence of ACTH and CRH, and the finding of an ACTH and a CRH concentration gradient across the tumor bed indicated that the tumor was actively secreting these two hormones. Cytochemical heterogeneity was seen in the tumor, in which two distinct populations of cells, one secreting ACTH and beta-endorphin and the other secreting CRH, were identified. This patient, thus, had an unusual syndrome of ectopic ACTH and ectopic CRH secretion.
Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.
The hypothalamic-pituitary-adrenal (HPA) axis underlies both adaptive and maladaptive responses to stress and may be an important marker of childhood vulnerability to psychopathology, although little is known about genetic variants that influence cortisol reactivity. We therefore examined associations between corticotrophin-releasing hormone (CRH) system gene (CRH, CRHR1 and CRHBP) variants and cortisol reactivity in preschoolers. A community sample of 409 three-year-old children completed a standardized stress task to elicit HPA axis activation. Salivary samples were obtained at the baseline and at 10-min intervals post-stress for a total of six samples. Salivary cortisol was measured using standard ELISA (enzyme-linked immunosorbent assay) protocols and cortisol reactivity was operationalized by calculating cortisol change scores ([baseline]-[peak cortisol post-stressor]). A single nucleotide polymorphism (SNP) marker panel containing 18 SNPs was used to tag the full-length CRH (4 SNPs), CRHR1 (7 SNPs) and CRHBP (7 SNPs) genes. Significant main effects on children's cortisol reactivity (all ps<0.05) were found for loci on CRHR1 and CRHBP. Haplotypes of the CRHR1 linkage region were also associated with cortisol reactivity (all ps<0.01). Additionally, we found multiple interactions between tag-SNPs in all three gene-coding regions predicting cortisol reactivity (all ps<0.05). Individual differences in children's cortisol reactivity are related to genetic variation in CRH system gene-coding regions. Our results have important implications for future research on the role of HPA axis function in the development of disorders such as anxiety and depression.
Classic nuclear-initiated estrogen signaling stimulates corticotropin-releasing hormone (CRH) gene expression as a transcription factor. However, the possible mechanism by which membrane-initiated estrogen signaling (MIES) influences CRH expression remains unclear. There are indications that MIES may upregulate nitric oxide (NO) production through the phosphatidylinositol 3-hydroxy kinase (PI3K) and potentially through the mitogen-activated protein kinase (MAPK) pathway.
Corticotropin-releasing hormone (Crh), a major mediator of the stress response, has been shown to exert both stimulatory and inhibitory effects on the regulation of the immune system, in vivo. In our present study, we used the Crh-/- mice to investigate the effect of Crh deficiency on leukocyte function in vitro. Our results show that following LPS treatment, TNF-alpha and IL-1beta expression was significantly compromised in Crh-/- splenocytes, an effect most likely mediated by the lower levels of NF-kappaB DNA binding activity measured in the same cells. Furthermore, we show here that the proliferation rate of Crh-/- splenocytes in response to LPS was decreased compared to Crh+/+ splenocytes. Taken together, our findings show that the presence of endogenous Crh is necessary for the normal function of leukocytes, in vitro.
Genistein is a phytoestrogen isolated from soya beans. Although soy products are staple food of Asian, the potential effect of genistein on reproduction has not been fully addressed. Lipopolysaccharide (LPS) is an endotoxin found in the cell membrane of gram-negative bacteria. It may cause inflammation and other immune responses. Previous study has shown that LPS may induce pre-mature birth in rodents. In the present study, effect of genistein on LPS-induced preterm birth was investigated. Pregnant ICR mice were gavaged with genistein at 40, 200 and 400 mg/kg body weight/day during E13 to E16. LPS was injected i.p. on E16.5 and the animals were sacrificed at E17. Compared to the control group, an increased incidence of early delivery was observed in the pooled mice under LPS treatment. A rising trend of incidence was also demonstrated dose-dependently with genistein co-treatment. Real-time RT-PCR indicated that the placental crh expression was highly induced by the co-administration of 400 mg/kg genistein and LPS. By contrast, neither genistein nor LPS alone could alter the expression. Increased plasma CRH concentration was also seen in the co-treatment groups. In addition, the mRNA expression of placental CRH-binding protein and plasma progesterone concentration were reduced in these groups. These results indicated that genistein might exacerbate the undesirable effect of LPS on pregnant mice by altering hormonal regulations.
Corticotropin-releasing hormone (CRH) acts mainly via the CRH receptor 1 (CRH-R1) and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS). Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients.
Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic-pituitary-adrenal (HPA) axis and the secretion of adrenal stress hormones. Previous work has demonstrated that stress hormone secretion can be regulated by circulating levels of estradiol. However, the effect of estradiol on CRH neuron excitability is less clear. Here, we show that chronic estradiol replacement following ovariectomy increases two types of potassium channel currents in CRH neurons: fast inactivating voltage-gated A-type K+ channel currents (IA) and non-inactivating M-type K+ channel currents (IM). Despite the increase in K+ currents following estradiol replacement, there was no overall change in CRH neuron spiking excitability assessed with either frequency-current curves or current ramps. Together, these data reveal a complex picture whereby ovariectomy and estradiol replacement differentially modulate distinct aspects of CRH neuron and HPA axis function.
Glutamate plays a role in the central regulation of the hypothalamic-pituitary-adrenal (HPA) and thyroid (HPT) axes. Until the recent discovery of vesicular glutamate transporters (VGLUT1-3), there was no specific tool for the examination of the putative morphological relationship between the glutamatergic and the hypophysiotropic systems. Using antisera against VGLUT2, corticotropin-releasing hormone (CRH), and prothyrotropin-releasing hormone (proTRH) (178-199), we performed double-labeling immunocytochemistry at light and electron microscopic levels in order to study the glutamatergic innervation of the CRH- and TRH-synthesizing neurons in the hypothalamic paraventricular nucleus (PVN). Fine VGLUT2-immunoreactive (IR) axons very densely innervated the parvocellular subdivisions of the PVN. VGLUT2-IR axons established juxtapositions with all parvocellular CRH- and TRH-synthesizing neurons. The innervation was similarly intense in all parvocellular subdivisions of the PVN. At ultrastructural level, VGLUT2-IR terminals frequently established synapses with perikarya and dendrites of the CRH- and proTRH-IR neurons. These findings demonstrate that glutamatergic neurons directly innervate hypophysiotropic CRH and TRH neurons in the PVN and, therefore, support the hypothesis that the glutamate-induced activation of the HPA and HPT axes may be accomplished by a direct action of glutamate on hypophysiotropic CRH and TRH systems.
It is a general consensus that stress is one of the major factors that suppresses growth. Previous studies revealed that the catecholaminergic and neuropeptide Y (NPY) systems, involved in the activation of stress-related neuronal circuits, influence growth hormone (GH)-release via modulating growth hormone-releasing hormone (GHRH) secretion. Indeed, catecholaminergic and NPY-immunoreactive (IR) axon varicosities abut on the surface of the GHRH neurons forming contacts. These juxtapositions appear to be real synapses and may represent the morphological substrate of the impact of stress on growth. In addition to catecholamines and NPY, there is a vast amount of evidence that corticotropin-releasing hormone (CRH), a major stress hormone, also influences GH secretion. Whether this modulatory effect is direct, or indirect, via the hypothalamic GHRH system, has not been elucidated yet. In the present study, we examined the possibility that CRH influences GH secretion via modulating the GHRH release by direct synaptic mechanisms. Since the verification of these synapses by electron microscopy is problematic in human due to the long post mortem time, in order to reveal the putative CRH-GHRH juxtapositions, light microscopic double label immunohistochemistry was utilized. In the infundibular nucleus, a subset (6%) of the GHRH perikarya received abutting CRH fiber varicosities forming multiple contacts while passing by. No gaps appeared between the contacting elements. The morphology of these CRH-GHRH juxtapositions suggests that, among other neurotransmitters/neuromodulators, CRH influences growth by modulating the hypothalamic GHRH secretion via direct synaptic mechanisms.
Corticotropin-releasing hormone (CRH) is known for its crucial role in the stress response system, which could induce pituitary adrenocorticotropic hormone (ACTH) secretion to promote glucocorticoid release in the adrenal gland. However, little is known about other pituitary actions of CRH in teleosts. Somatolactin is a fish-specific hormone released from the neurointermediate lobe (NIL) of the posterior pituitary. A previous study has reported that ACTH was also located in the pituitary NIL region. Interestingly, our present study found that CRH could significantly induce two somatolactin isoforms' (SLα and SLβ) secretion and synthesis in primary cultured grass carp pituitary cells. Pharmacological analysis further demonstrated that CRH-induced pituitary somatolactin expression was mediated by the AC/cAMP/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, transcriptomic analysis showed that both SLα and SLβ should play an important role in the regulation of lipid metabolism in primary cultured hepatocytes. These results indicate that CRH is a novel stimulator of somatolactins in teleost pituitary cells, and somatolactins may participate in the stress response by regulating energy metabolism.
A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light-dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.
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